Importance of Immunological and Inflammatory Processes in the Pathogenesis and THERAPY of Alzheimer's Disease

Inrem. J . Neuroscience. 1998. Vol. 95, pp 203-236 Reprints available directly from the publisher Photocopying permitted by license only

C 1998 OPA (Overscas Publishers Association) N.V. Publishcd by license undcr

the Gordon and Breach Science Publishers imprint.

Printed in India.

IMPORTANCE OF IMMUNOLOGICAL AND INFLAMMATORY PROCESSES

IN THE PATHOGENESIS AND THERAPY OF ALZHEIMER’S DISEASE *

MIROLJUB POPOVIC a,**, MARIA CABALLERO-BLEDA a, LUIS PUELLES a and NATALIJA POPOVIC

a Departamento de Ciencias Morfoldgicas y Psicobiologia, Facultad de Medicina, Universidad de Murcia, 30100 Espinardo (Murcia), Spain;

Immunology Research Center “Branislav JankoviC”, Vojvode Stepe 458, 11221 Belgrade, F R Yugoslavia

(Received in final form 13 April 1998)

The contribution of autoimmune processes or inflammatory components in the etiology and pathogenesis of Alzheimer’s disease (AD) has been suspected for many years. The presence of antigen-presenting, HLA-DR-positive and other immunoregulatory cells, components of complement, inflammatory cytokines and acute phase reactants have been established in tissue of A D neuropathology. Although these data do not confirm the immune response as a primary cause of AD, they indicate involvement of immune processes a t least as a secondary or tertiary reaction to the preexisting pathogen and point out its driving-force role in A D pathogenesis.

These processes may contribute to systemic immune response. Thus, experimental and clinical studies indicate impairments in both humoral and cellular immunity in an animal model of AD as well as in A D patients.

On the other hand, anti-inflammatory drugs applied for the treatment of some chronic inflammatory diseases have been shown to reduce risk of AD in these patients. Therefore, it seems that anti-inflammatory drugs and other substances which can control the activity of immunocompetent cells and the level of endogenous immune response can be valuable in the treatment of A D patients.

Keywords; Alzheimer’s disease; inflammation; neuroimmunomodulation; therapy

*This work was supported by a grant from the Spanish Ministry of Education and Science (DGICYT PB93-1137) to L. P. and by a grant from the Serbian Ministry of Science and Technology.

**Corresponding author.

203

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

204 M. POPOVIC et al.

Alzheimer’s disease (AD) is one of the most common types of dementia. It is defined as a neurodegenerative disease which is characterized by a progressive loss of intellectual abilities (memory, reasoning, judgement, perception and orientation), increased propensity to emotional disabilities (unexplained bouts of depression, anxiety, agitation or uncharacteristic indifference and apathy) and gradual decline of personality (McKhann, Drachman, Folstein, Katzman, Price and Stadlan, 1984; Jones and Richardson, 1990). It has been established that the immune responses of AD patients are altered, so that immunological alteration as well as inflammation start to be considered as an important component of AD pathogenesis (Gautrin and Gauthier, 1989; McGeer, Akiyama, Itagaki and McGeer, 1989a; Rogers, Webster, Lue, Brachova, Civin, Emmerling, Shivers, Walker and McGeer, 1996).

NEUROPATHOLOGICAL HALLMARKS OF ALZHEIMER’S DISEASE

The brain lesions which occur in AD and non-AD elderly people are qualitatively similar, but are present in much greater density and wider distribution in individuals suffering from AD. The neuropathological hallmarks of AD are cerebral cortical atrophy, loss of neurons, accumulation of paired helical filaments as neurofibrillary tangles in the perinuclear cytoplasm of neurons and amyloid fibrils in senile plaques as well as in the walls of blood vessels (Berg, McKeel, Miller, Baty and Morris, 1993). The brains of non-AD affected elderly people usually are characterized by amyloid deposition in the absence of neocortical neurofibrillary tangles and neuropil threads or synaptic pathology (Dickson, Crystal, Mattiace, Kress, Schwagerl, Davies, Yen and Aronson, 1989).

On the other hand, the degree and duration of AD are most closely in correlation with widespread formation of neurofibrillary tangles caused by abnormally phosphorylated cytoskeletal tau protein (Lee and Trojanowski, 1995). Moreover, the tangles typically appear at modulatory projection systems such as the cholinergic neurons of the nucleus basalis of Meynert (NBM), the noradrenergic neurons of the locus coeruleus and serotoninergic neurons of raphe nuclei (Perry, Tomlinson, Blessed, Perry, Cross and Crow, 1981; Curcio and Kemper, 1984; Yamamoto and Hirano, 1985; Rasool, Svendsen and Selkoe, 1986; Yankner and Mesulam, 1991).

The reduction in the number of neurons and synapses is mainly related to frontal, temporal and parietal lobes (Colon, 1973; Terry, Peck, DeTeresa, Schechter and Horoupian, 198 1; Hamos, DeGennaro and Drachman, 1989;

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

IMMUNOLOGY AND INFLAMMATION IN ALZHEIMER’S DISEASE 205

Masliah, Terry, DeTeresa and Hansen, 1989; Masilah, Terry, Alford, DeTeresa and Hansen, 1991), nbM (Whitehouse, Price, Struble, Clark, Coyle and DeLong, 1982; Coyle, Price and DeLong, 1983; Rogers, Brogan and Mirra, 1985; Saper, German and White, 1985), hippocampus (Ball, 1977), amygdala (Herzog and Kemper, 1980), locus coeruleus (Tomlinson, Irving and Blessed, 1981; Bondareff, Mountjoy and Roth, 1982; Mann and Yates, 1986) and raphe nuclei (Yamamoto and Hirano, 1985). A high density of senile plaques is also found in the same brain structures (Bowen, 1981; Perry and Perry, 1985; Yankner and Mesulam, 1991) and is not strictly related to the symptomatology of AD. However, it is thought that the density of senile plaques, as well as their form, are different in AD subjects compared to non-demented age-matched controls.

The main component of senile plaques appears to be insoluble deposits of extracellular amyloidogenic proteins which usually evolve from “diffuse” or “preamyloid” thioflavin- and congo-red-negative forms. These are the main type of amyloid deposit in the cerebral cortex of non-demented aged individuals. These deposits of non- or low-grade fibrillar amyloidogenic proteins show scarce or no surrounding dystrophic neurites or glia (Tagliavini, Giaccone, Frangione and Bugiani, 1988). During the progression from diffuse plaques through “immature” plaques, which already contain damaged neurites with paired helical filaments, fibrillogenesis and condensation of amyloidogenic proteins results in formation of a central compact core within the plaque. These “mature” thioflavin- and congo-red- positive plaques consist of a neuritic halo with a dense central amyloid core. The final stage in development of AD plaques is named “burned out”, being plaques composed of a prominent central amyloid core with few remaining peripheral neurites (Perry and Perry, 1985; Roberts, Lofthouse, Allsop, Landon, Kidd, Prusiner and Crow, 1988; Yankner and Mesulam, 1991). Fibrillar and compacted neuritic plaques are predominantly observed in cortex and hippocampus, whereas amyloidogenic deposits remain non- filamentous in other brain regions such as in thalamus, caudate nucleus, hypothalamus and cerebellar corte (Ogomori, Kitamoto, Tateishi, Sato, Suetsaga and Abe, 1989). Neurological symptoms of AD are related to brain regions with fibrillar deposits.

IMMUNOLOGICAL HYPOTHESES OF ALZHEIMER’S DISEASE

Although the cause of the above-mentioned pathomorphological changes is still unknown, detailed analysis have established many factors involved in the

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


development of AD which indicate the heterogeneous character of this disorder (in fact a syndrome). Besides age and genetic abnormalities (the most dominant risk factors), the contribution of autoimmune processes or inflammatory components in etiology and pathogenesis of AD has been suspected for many years (Gautrin and Gauthier, 1989; McGeer et al., 1989a).

There are several reasons why alterations of the immunological functions were proposed as a cause or pathophysiological factor in AD development (Fudenberg, Whitten, Arnaud and Khansari, 1984; McRae and Dahlstrom, 1992). The detection of amyloid deposits in and around the walls of cerebral blood vessels as well as in vessels of the dermis, subcutaneous tissue, small and large intestine and adrenal gland in individuals with AD and Down’s syndrome (Schwartz and Kurucz, 1965; Joachim, Mori and Selkoe, 1989) suggested that amyloid proteins originate systemically and then accumulate within the brain. These observations pointed out the parallelism of AD with systemic amyloidoses established in several autoimmune diseases such as myeloma and rheumatoid arthritis-RA (Glenner, 1980) as well as with amyloidosis of the elderly which were thought to be results of autoimmune processes (Schwartz and Kurucz, 1965). This assumption was supported by the evidence of increased levels of circulating autoantibodies against neuronal tissue in aging humans and subjects with AD as well as in aged experimental animals (Edgington and Dalessio, 1970; Felsenfeld and Wolf, 1972; Ingram, Phegan and Blumenthal, 1974; Nandy, 1978). Moreover, it was established that these occurs as a reduction of immunological competence with age (Burnet, 1970).

Concerning the immunopathology of AD, the parallelism between AD amyloidosis and the plaques found in some transmissible encephalopathies such as Creutzfeldt-Jakob disease, kuru and Gerstmann-Straussler syndrome in humans and scrapie in some animals species, was also noted (Beck and Daniel, 1969; Roberts et al., 1988; Gautrin and Gauthier, 1989; Barcikowska, Kwiecinski, Liberski, Kowalski, Brown and Gajdusek, 1995).

More convincing evidence for such an immune model of AD came from the report of Ishii and Haga (1 975). These authors reported the presence of immunoglobulin (Ig) G is senile plaques, indicating the possible implication of the immune system in the pathogenesis of amyloid fibrils. Several times after that, Ishii and his group (Ishii and Haga, 1976; Ishii and Haga, 1984; Ishii, Haga and Kametani, 1988), as well as other groups (Alafuzoff, Adolfsson, Grundke-Iqbal and Winblad, 1987; Powers, Schlaepfer, Will- ingham and Hall, 1981), obtained similar results, but it was concluded that immunostaining for IgG in senile plaques was an artifact of non-specific binding (Eikelenboom and Stam, 1982; Eikelenboom and Veerhuis, 1996).

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


However, it became clear that either diffuse amyloid deposits that often occur in AD cerebellum or the profuse tangles and compacted amyloid deposits that sometimes occur in non-demented patients, are not sufficient to cause neurodegeneration or clinical signs unless full-blown inflammatory reactions are also present.

AMYLOID PROTEINS AS A CAUSE OF AUTODESTRUCTIVE EVENTS

It is now known that autodestructive processes prominently expressed in AD can be caused by a direct neurotoxic effect of the primary constituent of these amyloid plaques, the P-amyloid peptide (PA4), and by a consequently induced cascade of inflammatory processes. In non-pathological conditions, the peptide PA4, a residue of 40-42 amino acids, is formed at low concentration by the action of a-secretase from the proteolytic cleavage of a large transmembrane glycoprotein termed amyloid precursor protein (APP). The concentrations of PA4 in cerebrospinal fluid (CSF) and plasma are 2.5 and 0.9 ng/ml, respectively (Kang, Lemaire, Unterbeck, Salbaum, Masters, Grzeschik, Multhaup, Beyreuther and Moller-Hill, 1987; Yankner and Mesulam, 1991; Sisodia and Price, 1993; Luo, Hirashima, Li, Alkon, Sunderland, Etcheberrigaray and Wolozin, 1995). The abnormal processing of the short-lived APP into the PA4 is thought to be caused by APP mutations, or an altered balance between proteases and protease inhibitors and/or between protein kinases and phosphatases (Masliah, Mallory, Ge and Saitoh, 1992).

Cell culture studies showed that in an increased, micromolar range, PA4 can self-aggregate and potentiates glutamate-mediated calcium influx in mature neurons through a process that requires extracellular matrix proteins. This activates a series of apoptotic or excitotoxic events for prolonged periods of time (Loo, Copani, Pike, Whittemore, Walencewicz and Cotman, 1993; Mattson, Tomaselli and Rydel, 1993). The PA4 peptide may also competitively inhibit the binding of extracellular proteases such as al-trypsin (alAT)-protease complex to the receptor for the serpin protease inhibitor-enzyme complex (SEC), impairing the capacity of neural cells to clear these proteases. The SEC receptor specifically recognizes the amino acid sequence 25 - 35 of PA4, which is homologous to the tachykinin family of neuropeptides, and could mediate both neurotrophic and neurotoxic effects (Yankner, Duffy and Kirschner, 1990; Yankner and Mesulam, 1991). An increase of the major alternative secreted forms of APP-695, transcripts

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

208 M. POPOVIC et a[.

APP-751 and APP-770, which contain an insert with strong homology to the Kunitz family of serine protease inhibitors (KPI) (Ponte, Gonzalez- DeWhitt, Schilling, Miller, Hsu, Greenberg, Davis, Wallace, Lieberburg, Fuller and Cordell, 1988), to protease nexin I1 (PN-II), (Oltersdorf, Fritz, Schenk, Lieberburg, Johnson-Wood, Beattie, Ward, Blacher, Dovey and Sinha, 1989; Van Nostrand, Wagner, Suzuki, Choi, Farrow, Geddes, Cotman and Cunningham, 1989) and to the platelet coagulation factor XIa inhibitor (Smith, Higuchi and Broze, 1990), may contribute in addition to pathogenic events in AD. Thus, it has been suggested that these portions of APP also regulate the binding of SEC to cell surface receptors as well as its internalization. Similarly to the protease nexins, binding to and suppressing neuronal surface proteases, they probably can mediate the initial stages of neurite outgrowth in affected areas of AD brain (Shea, 1995).

The involvement of APPs in the anchorage of the cells of the extracellular matrix (ECM) in senile plaques was also speculated upon and is thought to be based on their similarities to the heparan sulphate proteoglycan core protein (Vandenabeele and Fiers, 1991). Although PA4 serves as an anchorage site, in vitro studies have shown that the expression of ECM molecules such as fibronectin enhances the adherence of microglia, eliciting through them neurotoxicity with subsequently increased APP secretion. On the other hand, the expression of laminin and collagen inhibits the binding of microglia, leading to their deactivation (Monning, Sandbrink, Weide- mann, Banati, Masters and Beyreuther, 1995).

INVOLVEMENT OF ENDOGENOUS IMMUNE RESPONSE IN DEVELOPMENT OF ALZHEIMER’S DISEASE

Activated Microglia and Reactive Astrocytes and their Mediators

Sustained activation of microglia results in either production of amyloid de lzovo or uptake and processing by these cells of an amyloidogenic precursor (Castaiio and Frangione, 1988; Glenner, 1980; Itagaki, McGeer, Akiyama, Zhu and Selkoe, 1989). They also are able to present phagocytosed and processed antigens on their cell surfaces, bound to major histocompatibility complex (MHC) class I1 molecules (Abbas, Lichtman and Pober, 1991). Large numbers of such reactivated cells were detected postmortem by specific anti-human MHC I1 (HLA-DR) antibodies in patients with AD and aged individuals. Increased expression of HLA-DR in the brain of non- demented individuals was restricted to ramified microglial cells distributed

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


in an uniform reticular array in both gray and white matter. In AD cases, intense anti-HLA-DR labelling was established on activated microglia with plump somata and short thick processes, often clustered around neuritic plaques, neurofibrillary tangles and vascular walls, rather than in an uniformly distributed array (McGeer, Itagaki, Tag0 and McGeer, 1987; McGeer, Itagaki, Boyes and McGeer, 1988; Rogers and Luber-Narod, 1988; Rogers, Luber-Narod, Styren and Civin, 1988; Perlmutter, Scott, Barron and Chui, 1992; Aisen, 1996; Kalaria, Cohen and Premkumar, 1996; Lue, Brachova, Civin and Rogers, 1996). Somata of activated microglia stained darkly and appeared filled with dense cytoplasmic bodies and lipofuscin granules. In some instances, these cells were visualized phagocytosing debris of neurons and their processes (McGeer, Akiyama, Itagaki and McGeer, 1989b; McGeer, McGeer Kawamata, Yamada and Akiyama, 1991a).

Recent evidences have shown that microglia can also synthetize apolipoprotein E (ApoE) (Nakai, Kawamata, Taniguchi, Maeda and Tanaka, 1996). Previously, it was widely postulated that this lipoprotein originates mainly in astrocytes and then is taken up by neurons, most likely by receptor mediated endocytosis. As ApoE and PA4 share common antigenic determinants and have similar heparin binding domains, ApoE can bind to PA4 and promotes the formation of amyloid fibrils (Schmechel, Saunders, Strittmatter, Crain, Hulette, Joo, Pericak-Vance, Goldgaber and Roses, 1993; Strittmatter, Weisgraber, Huang, Dong, Salvesen, Pericak- Vance, Schmechel, Saunders, Goldgaber and Roses, 1993). Having in mind that astrocytes by themselves are also a source of APP (Card, Meade and Davis, 1988), these findings obviously indicate that microglia and astrocytes must be considered as very important contributors in the genesis of insoluble extracellular PA4 deposits (Nieto-Sampedro and Mora, 1994).

Additionally, some findings have shown that proteases of the cathepsin family and their inhibitors, called cystatins, detected in both neurons and glia cells, are also involved in the formation of APP (Bernstein, Bruszis, Schmidt, Wiederanders and Dorn, 1989; Cataldo, Barnett, Berman, Li, Quarless, Bursztajn, Lippa and Nixon, 1995; Lemere, Munger, Shi, Natkin, Haass, Chapman and Selkoe, 1995).

It has become evident that, activated by the PA4, specially by its N- terminal region, microglia cells are stimulated to release and express receptors for many different inflammatory cytokines, such as interleukin (IL) l a and 1P to IL-3, IL-6, IL-8, tumor necrosis factor-a (TNF-a) and colony stimulating factor (Vandenabeele and Fiers, 199 1; Nakajima and Kohsaka, 1993; Gebicke-Haerter, Appel, Taylor, Schobert, Rich, Northoff and Berger, 1994; Sheng, Mrak and Griffin, 1995). It has been proposed

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


that, in high concentration, some of these agents promote proliferation of surrounding microglial cells and astrocytes as well as intracellular over- production of APP. In turn, both types of activated glia producing IL-1 and IL-6 (Giulian, 1987; Nieto-Sampedro and Berman, 1987; Vandenabeele and Fiers, 1991; Nieto-Sampedro and Mora, 1994), enhance APP production by neurons and endothelium, which propagates the process of plaque formation. Moreover, activated astroglia cells produce on their own protein SlOOP (Marshak, Pesce, Stanley and Griffin, 1992; Sheng, Ito, Skinner, Mrak, Rovnaghi, Van Eldik and Griffin, 1996), which in turn increases neuronal intracellular levels of calcium (Barger and Van Eldik, 1992) and potentiates the direct neurotoxic effects of the PA4 peptides (Cotman, Pike and Copani, 1992). The resulting damage or neuronal death is not only mediated by overactivation of the glutamate receptors and the excessive influx of calcium ions (Giulian, Haverkamp, Yu, Karshin, Tom, Li, Kirkpatrick, Kuo and Roher, 1996), but in part by an oxidative stress mechanism resulting from increased production of reactive oxygen species and nitric oxide by activated microglia and astrocytes (Klegeris, Walker and McGeer, 1994; Rossi and Bianchini, 1996).

However, the major function of activated microglia is probably to attract and present foreign antigen together with MHC class I or I1 structures to CD4+ or CD8+ T lymphocytes, respectively (phenomenon of MHC restriction) (Abbas et al., 1991). As a result of this phenomenon, activated helper T-cells start to proliferate and produce numerous cytokines, the cytokines IL-2 being the central component related not only to the proliferation of these cells themselves, but also to further increase of MHC class I and I1 expression and mobilization of particular effector cells, such as suppressor/cytotoxic T lymphocytes, natural killer cells (NK cells), lymphokine-activated killer (LAK) cells and B lymphocytes (Gehrmann, Matsumoto and Kreutzberg, 1995; Hanisch and Quirion, 1996).

In such inflammated tissue within and around senile plaques, the intracellular adhesion molecule-1 (ICAM-1, CD54), as well as its ligand of the integrin family, the lymphocyte function associated antigen- 1 (LFA- 1) (CD1 la, p-2 integrin), have been detected, indicating that these activated T cells probably attach to activated endothelial cells and then migrate through the blood-brain barrier (Raine, Cannella, Duijvestijn and Cross, 1990; Perlmutter, Barrbn, Saperia and Chui, 199 1; Verbeek, Otte-Holler, Westphal, Wesseling, Ruiter and de Waal, 1994). Further investigations have also identified IL-2 receptors, leucocyte common antigen (LCA) and LFA-1 on glia cells (McGeer et al., 1987, Nieto-Sampedro and Chandy, 1987; McGeer et al., 1991a; Eizenberg, Faber-Elman, Lotan and Schwartz,

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

IMMUNOLOGY AND INFLAMMATION IN ALZHEIMER’S DISEASE 21 1

1995; Sawada, Suzumura and Marunouchi, 1995). With regard to this process of T lymphocyte transmigration, it has been proposed that cytokine secreting glial and T-cells activate local endothelial cells to express ICAM and other cell adhesion molecules, such as the platelet endothelial (PECAM) and vascular- 1 cell adhesion molecules (VCAM) (Lerner, Cohen, Pax, Friedland and Kalaria, 1993), which facilitates the migration of lymphocytes across the endothelium to the site of senile plaques.

However, despite the above mentioned occasional reports, it is generally accepted that T-cells are rarely found in senile plaques (Finch and Marchalonis, 1996). This sharply distinguishes plaques of AD from the inflammatory mechanisms of multiple sclerosis. Evidence that in AD brains the neuritic plaques can induce nonimmune-mediated chronic inflammatory response without influx of leucocytes from the blood into the neuropil can be correlated with findings that aggregated PA4 peptide can bind the collagen-like region of the C l q molecule of complement and activate the classical complement cascade (Rogers, Cooper, Webster, Schultz, McGeer, Styren, Civin, Brachova, Bradt, Ward and Lieberburg, 1992; Jiang, Burdick, Glabe, Cotman and Tenner, 1994; O’Banion and Finch, 1996).

Complement Proteins and Acute Phase Reactants

The presence of complement components Clq, C ~ C , C3d and C4d in AD amyloid deposits has been clearly established (Eikelenboom and Stam, 1982; Ishii and Haga, 1984; Eikelenboom, Hack, Rozemuller and Stam, 1989; McGeer et al., 1989a,b). On the contrary, the prion protein (PrP)- containing plaques in scrapie do not contain complement or other acute phase reactant proteins (Eikelenboom, Rozemuller, Kraal, Stam, McBride, Bruce and Fraser, 1991).

Components C1 and C3 probably are produced by microglia and astrocytes, whereas C4 originates predominantly from neurons (Johnson, Lampert-Etchells, Pasinetti, Rozovsky and Finch, 1992; Walker and McGeer, 1992). The degraded fragments of these components chemically bind to amyloid deposits and dystrophic neural elements and opsonize the tissue. In this process of complement-mediated cell lysis, the microglia is also actively involved. Having binding sites for C3 and C4, e . g . , CD1 lb and CD1 lc (p-2 integrins), respectively, the microglia is able to bind to targets in the extracellular matrix or on bilipid membranes of other cells and to facilitate the consequent chemotactic guidance and phagocytosis (McGeer et al., 1991a). The complex of the fragments derived from C2, C3 and C4

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

212 M. POPOVIC et a / .

may undergo a series of reactions which result in the formation of the membrane attack complex (MAC), C5-C9. Inserted into the cell membrane, the MAC would induce lysis and cellular death. Additionally, C5a can bind to receptors on microglia and cause oxidative burst activity, which implicates an important role of oxidative stress as a pathogenic route contributing to the progression of AD.

Contrary to the above-mentioned initial studies suggesting the presence of the MAC on dystrophic elements surrounding amyloid plaques, recent study with a panel of MAC-specific poly- and monoclonal antibodies have shown no immunohistochemical evidence for the presence of the late complement components C7 and C9 and the complement MAC in neuropathological lesions in AD brains (Eikelenboom and Veerhuis, 1996). These findings indicate that in AD the complement system does not act as an inflammatory mediator through the formation of MAC. Therefore, it is been proposed that P-amyloid converts acute phase injury response into chronic neurodegeneration through the early complement activation products and several other mechanisms (Chen, Frederickson and Brunden, I996 Cotman, Tenner and Cummings, 1996; Veerhuis, Janssen, Hack and Eikelenboom, 1996).

The mechanism of activation of this classical complement pathway without contribution of immunoglobulins is not yet clear (Rogers, Schultz, Brachova, Lue, Webster, Bradt, Cooper and Moss, 1992). However, it has been established that trypsin-like enzymes and compounds similar to heparin sulfate can initiate the complement activation. Having in mind that a local increase of such substances can be expected within and around senile plaques, it is possible that direct conjugation of the C lq component of C1 to aggregated P-amyloid starts the complement cascade (McGeer et al., 1991a; Vandenabeele and Fiers, 1991; Webster, Bonnell and Rogers, 1997).

Moreover, several other components of senile plaques have been reported to act as stimulator or regulator of complement activation (Duong, Nikolaeva and Acton, 1997; Schwab, Steele, McGeer and McGeer, 1997). Many of them are classified as acute phase reactant proteins. For example, serum amyloid P (SAP) and C-reactive proteins (CRP) are stimulators of complement activation (Osmand, Friedenson, Gewurz, Painter, Hofman and Shelton, 1977; Hind, 1986). They belong to the family of pentraxins. It is important to note that they are not produced in brain tissue and their mRNA is only evident in the liver (Kalaria, Golde, Cohen and Younkin, 1991). SAP and CRP are present in blood and are transported into the brain as a result of increased permeability or porosity of the blood-brain barrier or through transcytotic mechanisms (Kalaria, 1992). SAP also can be involved

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

IMMUNOLOGY AND INFLAMMATION IN ALZHEIMER'S DISEASE 21 3

in the deposition and fibrillogenesis of amyloid deposits (Togashi, Lim, Kawano, Ito, Ishihara, Okada, Nakano, Kinoshita, Horie, Episkopou, Gottesman, Costantini, Shimada and Maeda, 1997) and in calcium- dependent binding of a variety of molecules, such as heparan- and dermatan-sulphat, which participate in these deposits. Thus, SAP exhibits high calcium-dependent affinity and binds to PA protein, as well as to CI, and C4 binding protein (Bristow and Boackle, 1986; Kalaria, 1993; Tennent, Lovat and Pepys, 1995).

On the other hand, the C l inhibitor (Cl-Inh) was also identified in A D brain tissue (Walker, Yasuhara, Patston, McGeer and McGeer, 1995). It belongs to the serpin (serine protease inhibitor-SRP) superfamily and inactivates, besides C 1, several other targets: kallikrein, plasmin and the coagulation factors XIa and XIIa. It therefore controls activation of a number of inflammatory proteolytic mechanisms. The C4-binding protein (C4bp), which regulates complement activation at the C3 level by dissociating activated C2 from C4, is also expressed in the brain. C4bp can be found in classical plaques, neurofibrillary tangles and blood vessels of the cerebral cortex of the AD brain (Eikelenboom and Veerhuis, 1996).

Interestingly, other proteins which protect host tissue against a MAC attack, such as protectin (CD59), vitronectin and clusterin (Apo J), are found to be upregulated in A D (Akiyama, Kawamata, Dedhar and McGeer, 1991; McGeer, Walker, Akiyama, Kawamata, Guan, Parker, Okada and McGeer, 1991b; McGeer, Kawamata and Walker, 1992a). Clusterin may prevent PA4 aggregation; its association with OA, found in CSF, may maintain the solubility of PA in biological fluids. However, some reports indicate that coaggregation of 3A4 with clusterin can be even more toxic than aggregated PA4 alone. Namely, clusterin may keep PA in a soluble aggregated form that can diffuse extensively, leading to damage of distal neurons independent of plaques (Choi-Miura and Oda, 1996).

Besides that, some specific protease-inhibitors, such as a l-antichymotrypsin, tr l-antitrypsin and a2-macroglobulin, presumably have protective effects against inflammatory protease damage (Bauer, Strauss, Schreiter- Gasser, Genter, Schlegel, Witt, Volk and Berger, 1991; Vandenabeele and Fiers, 1991; Kalaria, 1993; Van Gool, De Strooper, Van Leuven, Triau and Dom, 1993; Verbeek et ul., 1994). The a2-macroglobulin is also a potent inhibitor of a2-secretase (Ganter, Strauss, Jonas, Weidemann, Beyrenther, Volk, Berger and Bauer, 1991) and acts as the low-density lipoprotein receptor-related protein (LRP), localized predominantly in neurons and in a lesser degree in glial cells (Businaro, Fabrizi, Persichini, Starace, Ennas, Fumagalli and Lauro, 1997). The function of this a2-macroglobulin is

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

214 M. POPOVIC et UI.

presumed to be the capture of ApoE, aiding its processing by the endosomal-lysosomal pathway (Moestrup, Gliemann and Pallesen, 1992; Tooyama, Kawamata, Akiyama, Moestrup, Gliemann and McGeer, 1993; Ma, Brewer, and Potter, 1996). However, al-antichymotrypsin can also act as a chaperone, binding to PA and promoting its polymerization into mature amyloid filaments (Das and Potter, 1995). These interactions are analogous to the association of ApoE with PA (Kalaria, Harshbarger-Kelly, Cohen and Premkumar, 1996).

It has been proposed that the secretion and deposition of these acute- phase proteins found in AD is caused by the increased concentration of IL- 1/IL-6 (Vandenabeele and Fiers, 1991). Activated microglia cells are the major source of IL-1 production. The increased release of IL-1P induces the synthesis of IL-6, probably mediated by Ca2+ ions, which in turn increase the synthesis of class 2 acute phase proteins such as al-antichymotrypsin, al-antitrypsin and a2-macroglobulin (Ganter et al., 1991; Wood, Wood, Ryan, Graff-Radford, Pilapil, Robitaile and Quirion, 1993). The combina- tion of IL-6 and IL-1 can stimulate astrocytes to increase the synthesis of class 1 acutephase reactants, including CRP and complement C3, which in correlation with other activated components of complement, contribute to widespread “bystander neuronal lysis”.

Having in mind that IL-1 and IL-2 have mitogenic effects on astrocytes, allowing them to proliferate and form a robust glial scar, it is not surprising that only GFAP-reactive astrocytes, spongioform tissue, or simple atrophy may be found in lesioned tissue in late stages of AD. The HLA-DR-positive macrophages may then have disappeared, which indicates that a strong HLA-DR reaction is only a premonitory of the progression of this disease (McGeer et al., 1988).

Potential Final Consequences of an Inflammatory State

The processes of exacerbation in the late stages of the disease have not been investigated enough, but it has been noted that only subtle prevalence between wound healing effects and neurodestructive forces might be of crucial importance for the outcome. Namely, it has been shown in vitro that PA can either stimulate neurite outgrowth or cause cellular degeneration, depending of its assembly state. Many cytokines and other proteins detected in lesioned brain tissue may have also neuroprotective effects. Among these substances are the transforming growth factor Q and Pl (TGF-Q and TGF- p l ) (Van der Wal, G6mez-Pinilla and Cotman, 1993; Ferrer, Alcantara, Ballabriga, Olive, Blanco, Rivera, Carmona, Berruezo, Pitarch and Planas,

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

IMMUNOLOGY AND INFLAMMATION IN ALZHEIMER’S DISEASE 21 5

1996), the basic fibroblast growth factor (bFGF) (Stopa, Ghzalez , Chorsky, Corona, Alvarez, Bird and Baird, 1990), the hepatocyte growth factor (HGF) (Yamada, Tsubouchi, Daikuhara, Prat, Comoglio, McGeer and McGeer, 1994; Yamada, Yoshiyama, Tsuboi and Shimomura, 1997) and epidermal growth factor (EGF) (Ferrer, Alcantara, Ballabriga, Olive, Blanco, Rivera, Carmona, Berruezo, Pitarch and Planas, 1996). The toxicity of PA4 can be attenuated, for example, by tumor necrosis factor a! and P (TNF-a! and TNF-P) (Barger, Horster, Furukawa, Goodman, Krieglstein and Mattson, 1995). TGF-P also modulates the actions of bFGF on cells and protects the extracellular matrix, which in turn, by means of proteoglycans, potentiates the action of growth factors.

IL-6 can enhance the spontaneous secretion of neuronal growth factor (NGF) by astrocytes, thus supporting neuronal survival (Frei, Malipiero, Leist, Zinkernagel, Schwab and Fontana, 1989; Gadient and Otten, 1997). IL-1 may directly or indirectly effect the growth of neurites and the concomittant increase in APP synthesis through the actions of protein Sloop or of neurotrophic fragments of APP.

Glycation of extracellular proteins itself may contribute to stabilization, aggregation and insolubility of the fibrillar proteins that constitute sensile plaques and neurofibrillary tangles in AD. Advanced glycation endproducts (AGE) seem to be removed from extracellular proteins by proteases released from macrophages under the influence of proinflammatory cytokines. Alternatively, macrophages may take up and degrade intracellularly the AGE-protein complexes, a process that may also lead to production of proinflammatory cytokines and release of other mediators of tissue injury (Dickson, Sinicropi, Yen, KO, Mattiace, Bucala and Vlassara, 1996; Thorpe and Baynes, 1996; Du Yan, Zhu, Fu, Yan, Tourtellotte, Rajavashisth, Chen, Godman, Stern and Schmidt, 1997).

The protease PNII, known to be homologous to certain secreted isoforms of APP, binds to and suppresses neuronal surface protease, stimulating the initial, non-target mediated, stage of neurite outgrowth (Shea, 1995). If we add to this that some acute-phase proteins also act as neurite growth promoting agents (May and Finch, 1992; Wagner, Geddes, Cotman, Lau, Gurwitz, Isackson and Cunningham, 1989), while the generation of plasminogen activators is inhibited (Akiyama, Ikeda, Kondo, Kato and McGeer, 1993) in favour of the thrombin system (inhibitor of neurite outgrowth), specially of its complex with PNI (Wagner et al., 1989; Akiyama, Ikeda, Kondo and McGeer, 1992), the interpretation of the mechanisms involved in brain damage appears to be come still more difficult.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

216 M. POPOVIC et al

Neurons can be stimulated to grow out neurites, predominantly in initial stages of AD. During the progression of the disease, the unavailability of appropriate targets, because of imposed reactive astrocytes and glial “scars” and/or deficiencies of neurite growth-promoting factors or their disregula- tion, probably aborts the sprouting and leads to further spread of neuronal degeneration and to the exacerbation of AD (Shea, 1995). The inflammatory response stimulated by AD lesions is self-amplified and, when it reaches a threshold, produces destruction of viable surrounding brain tissue. This suggests that there is a state of chronic inflammation in AD, which can proceed even without stimulation by the peripheral immune system and its mediators. Therefore, the question whether these localized chronic inflammatory processes can either alter the systemic immune response or be under the influence has become the subject of many clinical and experimental investigations.

HUMORAL AND CELLULAR IMMUNITY IN EXPERIMENTAL AND CLINICAL INVESTIGATIONS

Experimental Data

Numerous data suggest the importance of studying the interrelationships between the central nervous system and the immune system, as well as between the endocrine and immune systems (Fauman, 1982; JankoviC and Spector, 1986; Jankovid, MarkoviC and Spector, 1987; JankoviC, Jovanova- Neiid, and MarkoviC 1988; Blalock, 1989). It is well known that lesions or stimulation of the hypothalamic area, amygdaloid complex, hippocampus, neocortex, locus coeruleus, mamillary bodies and reticular formation, as well as the superior colliculus, may modify immune function (Khai, Kovalenkova, Korneva and Seranova, 1964; Korneva and Khai, 1964; Poliak, Rumbesht and Sinichkin, 1969; Macris, Schiavi, Camerino and Stein, 1970; Tyrey and Nalbandov, 1972; Cross, Brooks, Roszman and Markesbery, 1982; Renoux, Biziere, Renoux and Guillaumin, 1983; Renoux, Biziere, Renoux, Guillaumin and Degenne, 1983; Abramsky, Wertman, Reches, Brenner and Ovadia, 1987; Neveu, 1988; Neveu, Barneoud, Georgiades, Vitiello, Vincendeau and Le Moal, 1989; Jovanova- NeSiC, NikoliC and JankoviC, 1993; Nikolid, Javanova-NeSid and Jankovid, 1993; Vlajkovid, Nikolid, NikoliC, Milanovid and Jankovid, 1994).

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

IMMUNOLOGY A N D INFLAMMATION IN ALZHEIMER’S DISEASE 217

Humoral Immunity

There are only few reports related to immune response in experimental models of AD. It was found that electrolytic lesions of nucleus basalis magnocellularis (NBM) slightly (RadoSevid-StaSid, Cuk, Mrakovtid-Sutid, TrobonjaEa, Salamon, Stojanov, Rukavina, Zupan and Simonid, 1990) or significantly depressed (Popovid, Jovanova-NeSid and Popovid, 1995; Popovid, Jovanova-NeSid, PopoviC, UgreSid, Kostid and Rakid, 1997) humoral immunity after sensitization of rats with sheep red blood cells (SRBC).The electrolytic NBM-lesion significantly decreased serum hemag- glutinin titer in SRBC-immunized rats, (Popovid et al., 1995 Popovid et al., 1997). Besides that, the Arthus skin reaction to bovine serum albumin (BSA), as well as the anti-BSA antibody titer, were significantly reduced after electrolytic lesions of NBM (Popovid et al., 1995; Popovid et al., 1997). Moreover, the relative weights of the thymus and spleen, four days, after SRBC immunization, were significantly lower in NBM-lesioned rats (Popovid et al., 1997).

Cellular Immunity

Similarly to humoral immunity, the data related to cell-mediated immunity in experimental models of AD are also inconsistent.

It has been shown that electrolytic lesions of NBM in rats cause the prolongation of the rejection time of allogenic skin grafts (RadoSevid-StaSid et al., 1990). Suppression of cellular immunity after electrolytic lesions of NBM in rats was also detected by Popovid and colleagues (1997). They reported a significant reduction of delayed hypersensitivity skin reaction to BSA.

The proliferation of T-lymphocytes induced by concanavalin A (Con A), as well as the production of IL-2 induced by ConA- stimulated spleen lymphocytes, were higher in excitotoxic NBM-lesioned rats compared to control animals (Cherkaoui, Mayo, Neveu, Kelley, Vitiello, Le Moal and Simon, 1990). Moreover, natural killer-cell activity in the spleen was high in bilaterally NBM-lesioned rats (Cherkaoui et al., 1990). In contrast, results obtained in monkeys indicate that excitotoxic lesion of NBM induces depression of natural killer-cell activity (Kraus, Moss and Rosene, 1985). The reason of the observed inconsistencies may be related to the differences in the type of lesions, the duration and intensity of the electric current applied, as well as the duration of the recovery period after lesioning.

Morphological studies suggest that NBM is well connected with several brain regions: locus coeruleus, raphe nuclei, ventral tegmental area,

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


mediodorsal thalamus, hypothalamus, basolateral amygdala, limbic com- partment of striatum, hippocampal formation, paralimbic cortex and neocortex (Wenk, 1989). Since some of them have a significant immunomodulatory role, it is possible that the changes of the immune function after NBM-lesions in experimental animals may be related to an immunomodulatory role of NBM itself or to changes in the function of linked immunomodulatory brain structures.

Clinical Data

Similarly to experimental data, most clinical studies related to immunological parameters in AD patients show conflicting results. However, these results are more related to humoral than to cellular immunity.

Humoral Immunity

The first immunological investigations showed increased serum gammaglo- bulin and low serum albumin in AD patients (Behan and Feldman, 1970; Kalter and Kelly, 1975). Further studies found the increase of serum IgG only in patients with late-onset AD (Henschke, Bell and Cape, 1979) whereas a decrease of IgM was observed in presenile AD (Tavolato and Argentiero, 1980). However, some studies were not able to detect immunoglobulin in the CSF of subjects suffering from AD (Jonker, Eikelenboom and Tavenier, 1982). Interestingly, increased levels of serum IgG and IgA have been established in cognitively impaired individuals (Cohen and Eisdorfer, 1980; Eisdorfer and Cohen, 1980) but there were no significant differences in the serum immunoglobulins between the AD and the age-matched controls (Araga, Kagimoto, Funamoto and Takahashi, 1991).

However, AD patients have been found to have not only high titers of autoantibodies directed to non-brain antigens (antibodies to thyroglobulin and thyroid microsomal antigen, anti-nuclear antibodies, antibodies to smooth muscle, mitochondria and gastric parietal cell), often found in aged controls (Watts, 1985; McRae-Degueurce, Haglid, Rosengren, Wallin, Blennow, Gottfries and Dahlstrom, 1988; Ounanian, Gilbert, Renversez, Seigneurin and Avrameas, 1990; Lopez, Rabin and Huff, 1991; Genovesi, Paolini, Marcellini, Vernillo, Salvati, Polidori, Ricciardi, de Nuccio and Re, 1996), but also anti-brain autoantibodies (Singh and Fudenberg, 1986; Schott, Wormstall, Dietrich, Klein and Batra, 1996; Loeffler, Juneau, Nguyen, Najman, Pomara and LeWitt, 1997; Singh, 1997). It has been established that they are mainly of IgG3 class (McRae-Degueurce, Booj,

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


Haglid, Rosengren, Karlsson, Karlsson, Wallin, Svennerholm, Gottfries and Dahlstrom, 1987; Singh and Fudenberg, 1989).

The specificity of the antigens with which these autoantibodies react has not been clarified yet. It has been suggested that, in part, they are directed against cholinergic-specific antigens of the brain. Namely, sera or CSF from some patients with AD recognize cholinergic regions of human as well as rat central nervous system (CNS) (nuclei of neurons and some glial cells) (McRae, Ling, Polinsky, Gottfries and Dahlstrom, 199 1) and partially inhibit choline acetyltransferase (ChAt) activity in rat brain homogenates (Fillit, Luine, Reisberg, Amador, McEwen and Zabriskie, 1985). Besides that, antibodies which specifically lysed cholinergic synaptosomes by a complement mediated mechanism were detected in a subset of AD patients (Foley, Bradford, Docherty, Fillit, Luine, McEwen, Bucht, Winblad and Hardy, 1988). AD serum antibodies can also react to specific antigen from spinal cord motor neurons (McRae-Degueurce et al., 1987), as well as from cholinergic Torpedo electromotor neurons (Chapman, Bachar, Korczyn, Wertinan and Michaelson, 1988).

In addition to that, AD serum stain moderately Schwann cells and fibroblasts in human dorsal root ganglion (DRG) cultures, as well as oligodendrocytes, astrocytes and weakly fibroblasts in rat neonatal (.3 - 6 day-old rats) cerebellum cultures (Watts, Kennedy and Thomas, 1981). Therefore, the finding of a high titer of anti-GFAP IgM antibody and the prevalence of disease-specific anti-GFAP IgG against bovine spinal cord in sera of patients with AD is not surprising. The possible explanation for this is that activated T-cells switch from IgM antibodies to the IgG class (Tanaka, Nakamura, Takeda, Tada, Suzuki, Morita, Okado, Hariguchi and Nishimura, 1989).

It has been thought that the presence of IgG in CSF and serum of AD subjects might be in correlation with the BBB disruption, since IgG-species in the serum of some AD patients can react with vascular proteoglycan antigens on small blood vessels and capillaries in the brain (Fillit, Kemeny, Luine, Weksler and Zabrieskie, 1987; Michaelson, Chapman, Bachar, Korczyn and Wertman, 1989; Lopez et al., 1991).

In relation to findings of a high glucose metabolism of B-cells in AD patients, as well as of a hyperactive production of IgG and IgM against antigens in brain tissue (Kalter and Kelly, 1975), in vitro studies were performed on multiple Epstein-Barr virus (EBV)-transformed B cell lines derived from both AD patients and age-matched controls (Kingsley, Gaskin and Fu, 1988). Thus, i t was confirmed that these cell lines secrete antibodies with reactivity to specific brain structures of AD patients: neurofibrillary

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


tangles (NFT) in the middle temporal gyrus (rich in neuritic plaques and NFT) and astrocytes in the gray matter (but not with astrocytes in white matter of the same AD brain) (Kingsley et al., 1988) as well as to P-amyloid in amyloid plaques and blood vessels (Xu and Gaskin, 1997). Therefore, these investigations can also provide a valuable clue to the diagnosis of AD.

Cellular Immunity

Considering cellular immunity, AD induces a decrease in the suppressor lymphocyte population as well as a reduced suppressor cell function (Leffell, Lumsden and Steiger, 1985; Skias, Bania, Reder, Luchins and Antel, 1985), although some authors reported a normal cellular immune system (Behan and Feldman, 1970; Kalter and Kelly, 1975; Henschke et al., 1979).

In terms of T lymphocyte function, their proliferation in response to stimulation with T-cell mitogens (phytohemagglutinin, concavalin A) was depressed in many patients with AD (Miller, Neighbour, Katzman, Aronson and Lipkowitz, 1981; Singh and Fudenberg, 1986). The proliferative response of T-cells induced by B cells or monocytes in the autologous-mixed leucocyte reaction (AMLR) was increased in some AD patients, compared to age-matched controls (Leonardi, Arata, Bino, Caria, Farinelli, Parodi, Scudeletti and Canonica, 1989), while the number of autologous rosette-forming cells (ARFCs) was reduced (Khansari, Whitten, Chou and Fudenberg, 1985).

However, further studies have shown that the T/B and CD4+/ CD8+ratios do not differ between AD and control aged-matched healthy subjects. Nevertheless, the ratio of CD4+CD45R+ T-cells in the AD group was lower than in the control group, and the ratios of CD4+CD45RP T- cells and CD4+HLA-DRt T-cells were significantly higher in the AD group. Moreover, in comparison to the control group, in the AD group, the ratios CD4+CD45R+/CD4+ and CD4+CD45RP/CD4+ were lower and higher, respectively (Ikeda, Yamamoto, Takahashi and Yamada, 1991 a). Since the CD4+CD45R+ T-cells are involved in cellular immunity and the CD4+CD45RP T-cells in humoral immunity, having a major role in the helper activity of B cells for IgG production, the changed ratio of these subsets in AD patients may indicate an activated humoral immunity as well as decreased cellular immunity. The high percentage of CD4+HLA-DR+ and CD45R+ T-cells in the peripheral lymphocytes suggests that the immune reactions occurring in the brain of AD patients are probably reflected in the peripheral immune system (Ikeda et al., 1991a).

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

IMMUNOLOGY AND INFLAMMATION IN ALZHEIMER'S DISEASE 221

I n relation to this concept are the reports of an increased number of lymphocytes which express IL-2R in peripheral blood. Moreover, it was found that the presence of IL-2R was related to the CD4+ and CD8+ T- cells (Ikeda, Yamamoto, Takahashi, Kaneyuki and Yamada, 1991b). Nevertheless, the levels of serum IL-2 and IFN-a are got changed in subjects with AD, in comparison to the aged-matched normal controls (Araga et al., 1991; Esumi, Araga and Takahashi, 1991), and there is no significant difference in the IL-2 production by peripheral blood lymphocytes (Bessler, Sirota, Hart and Djaldetti, 1989). However, these cells produce less IL-1 in patients with AD (Khansari et al., 1985). On the other hand, the levels of IL-1 (Cacabelos, Barquero, Garcia, Alvarez and Vareva de Seijas, 1991) and al-antichymotryspin significantly increase (Lieberman, Schleissner, Tachiki and Kling, 1995) and IL-6 decreases in the CSF in patients suffering from AD (Yamada, Kono, Umegaki, Yamada, Tguchi, Fukatsu, Nakashinia, Nishiwaki, Shimada, Sugita, Yamamoto, Hasegawa and Nabeshima, 1995). Some other authors, did not detect changes (Bauer et al., 1991) or even increase (Kalman, Juhasz, Laird, Dickens, Jardanhazy, Rimanoczy, Boncz, Parry-Jones and Janaka, 1997) in the level of IL-6 in the serum or CRF of these patients.

In contrast to the established normal concentrations of some cytokines, such as IL-2 and IFN-a, natural killer (NK) cells showed significantly lower activity in the serum of patients with AD than in the normal controls (Araga pi d., 1991). The reduced activity of N K cells may be result of structural abnormalities observed in platelets of AD patients (Zubenko, Cohen, Boller, Malinakova, Keefe and Chojnacki, 1987), or of an abnormal intracellular metabolism reported in fibroblasts (Sims, Finegan and Blass, 1987; Araga et a/ . , 199 1: Sorbi, Piacentini, Latorraca, Piersanti and Amaducci, 1995). However, interferon-gamma-stimulated NK cytotoxicity is higher in AD patients in comparison to health elderly subjects (Solerte, Fioravanti, Severgnini, Pezza, Locatelli, Cerutti, Terenzi and Ferrari, 1997). In addition to these fundamental cellular and molecular aberrations noticed in AD, it has been reported a reduced number of muscarinic and nicotinic binding sites (Khansari et u/., 1985) and increased number TNF-0 receptors in the lymphocytes of AD patients (Bongioanni, Romano, Sposito, Castagna, Boccardi and Borgna. 1997).

Therefore, the exploration of changes in these cells as well as in other parameters of immunological function in relation with the stage and degree of the disease, should provide valuable clues to the diagnosis and therapy of AD.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

222 M. POPOVIC et

THERAPEUTIC APPROACH

Several pharmacologic strategies have been used in attempts to treat AD. Short-term strategies (neurotransmitter replacement strategies) were based on drugs that act on the cholinergic system (to improve memory and perhaps attention) or on bioamine systems (to improve noncognitive behavioral symptoms). Unfortunately, the obtained results have been somewhat disappointing (Kumar and Calache, 1991; Whitehouse, 1991). In the last few years, advances in biological research and increasing knowledge of the pathophysiological mechanisms involved in the development of AD (Blass and Gibson, 1991; Blass, KO and Wisniewski, 1991; Coria, Rubio and Bayon, 1994; Dodd, Scott and Westphalen, 1994) originated some alternative therapeutic approaches (Donoso, 199 1 ; Her- mann, Stern, Losonzcy, Jaff and Davidson, 1991; Whitehouse, 1991; Dresse, Marechal, Scuvee-Moreau and Seutin, 1994; Giacobini, 1994; Gottfries, 1994; Frolich and Riederer, 1995; Jane, 1995; Kisilevsky, 1996; Parnetti, Senin and Mecocci, 1997). One of these approaches based on the evidence of the involvement of the immune system and inflammation in AD (Breitner, 1996; Aisen, 1996; Aisen, 1997).

In this sense, further studies should address the neuropathology of AD resulting from neurotoxic microglia activity. There are some possible strategies: (1) to halt the excess release of PA4, (2) to prevent the deposition and fibrillisation of PA4 in senile plaques, (3) to suppress the cascade of cellular events which lead to microglia activation, (4) to inhibit the synthesis and secretion of neurotoxins by microglia, and (5) to block the actions of neurotoxins on the neurons (Giulian et al., 1996; Solomon, Koppel, Hanan and Katzav, 1996).

There is a growing number of experiments aiming to identify the specific domains of the PA4 peptide which can be used to block competitively the induction of activated microglia. Some anti-inflammatory drugs have been examined in an attempt to inhibit the neurotoxic effect of the already activated microglia.

The low rate of concomittant diagnoses of rheumatic arthritis (RA) and AD noticed by Jenkinson, Bliss, Brain and Scott (1989) also was discussed by McGeer et al. (1990, 1992b). Since RA patients were on long-term treatment with non-steroidal anti-inflammatory drugs (NSAIDs), corticos- teroids, methotrexate or other anti-inflammatory agents, it was thought that such drugs may be useful in preventing or delaying the onset of the symptoms of the dementia (McGeer, McGeer, Rogers and Sibley, 1990; McGeer, McGeer and Rogers, 1992b; Schnabel, 1993; Breitner, Gau, Welsh,

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


Plassman, McDonald, Helmas and Anthony, 1994; Eikelenboom, Zhan, van Goo1 and Allsop, 1994; Lucca, Tettamanti, Forloni and Spagnoli, 1994; Rich, Rasmusson, Folstein, Carson, Kawas and Brandt, 1995; McGeer, Schulzer and McGeer, 1996).

A 6-months-long, double-blind, placebo-controlled study demonstrated that AD patients treated with the NSAID indomethacin express significantly less cognitive decline than the AD patients which received a placebo (Rogers, Kirby, Hempelman, Berry, McGeer, Kaszniak, Zalinski, Cofield, Mansukhani, Wilson and Kogan, 1993). The mechanisms of action of NSAID are related to the supression of the action of cyclooxigenases, which catalyze the synthesis of prostaglandins (Smith, Borgeat and Fitzpatric, 1991; Smith and Marnett, 1991; Vane and Botting, 1987; Vane, 1994) and are strongly involved in excitotoxic cell-death via glutamatergic NMDA- type receptors (Breitner, 1996; Pasinetti, 1996). Therefore, antagonists of NMDA receptors have been also suggested to be useful for blocking the action of some neurotoxins secreted by activated microglia. However, the increased risk of gastrointestinal ulceration and bleeding (Soll, Weinstein, Kurata and McCarthy, 1991) limits the use of NSAID in the treatment of AD.

The finding that the presence of histamine is related to glutamate-induced excitotoxicity (Sunami and Tasaka, 1991) was the base for the investigation of H2-receptor antagonists in the same contex. The obtained results were similar to those observed after NSAID treatment of AD patients (Breitner Welsh, Helms, Gaskell, Gau, Roses, Pericak-Vance and Saunders, 1995).

Many immunomodulatory drugs such as interleukins, interferons or thymic hormones may be used to potentiate the depress cell-mediated immunity, while immunosuppressant agents such as cyclosporin A can be applied in patients having autoantibodies to brain-tissue antigens.

However, the main aim in the immunotherapeutic strategy for AD must be directed to interfere the microglial cytotoxicity in the early, still potentially reversible stage of AD. Since a complement-mediated inflammatory response is thought to be the thresholding phenomenon, but may be neuroprotective below a certain intensity level, proper antiinflammatory treatment must be applied at adequate times; otherwise it could be harmful. Pharmacological agents able to control the brain levels of complement factors and other endogenous immune substances, or which stimulate the production of neuropromoting factors, will be valuable in the treatment of AD. Thus, much further research is needed in order to develop an appropriate intervention procedure upon the immunopathological processes of AD.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

224 M. POPOVIC et a/.

References

Abbas, A. K., Lichtman, A. H. & Pober, J. S. (1991). Cellular and Molecular Immunology, Philadelphia: W. B. Saunders Company.

Abramsky, O., Wertman, E., Reches, A., Brenner, T. & Ovadia, H. (1987) Effect of hypothalamic lesions on experimental autoimmune diseases in rats. Annals of the New, York Academy of Sciences, 496, 360- 365.

Aisen, P. S. (1996) Inflammation and Alzheimer disease. Molecular and Chemical Neuropathol-

Aisen, P. S. (1 997) Inflammation and Alzheimer’s disease: Mechanisms and therapeutic strategies, Gerontology, 43, 143 - 149.

Akiyama, H., Kawamata, T., Dedhar, S. & McGeer, P. L. (1991) Immunohistochemical localization of vitronectin, its receptor and beta-3 integrin in Alzheimer brain tissue. Journal of Neuroimmunology, 32, 19 - 28.

Akiyama, H., Ikeda, K., Kondo, H. & McGeer, P. L. (1992) Thrombin accumulation in brains of patients with Alzheimer’s disease. Neuroscience Letters, 146, 152 - 154.

Akiyama, H., Ikeda, K., Kondo, H., Kato, M. & McGeer, P. L. (1993) Microglia express the type 2 plasminogen activator inhibitor in the brain of control subjects and patients with Alzheimer’s disease, Neuroscience Letters, 164, 233 - 235.

Alafuzoff, I., Adolfsson, R., Grundke-Iqbal, I. & Winblad, B. (1987) Blood-brain barrier in Alzheimer dementia and in non-demented elderly. An immunocytochemical study. Acta Neuropathologica (Berlin), 73, 160 - 166.

Araga, S., Kagimoto, H., Funamoto, K. & Takahashi, K. (1991) Reduced natural killer cell activity in patients with dementia of the Alzheimer type, Acta Neurologica Scandinavica.

Ball, M. J. (1 977) Neuronal loss, neurofibrillary tangles and granulovascular degeneration in the hippocampus with ageing and dementia. A quantitative study, Acta Neuropathologicu (Berlin), 37, 111-118.

Barcikowska, M., Kwiecinski, H., Liberski, P. P., Kowalski, J., Brown, P. & Gajdusek, D. C. (1 995) Creutzfeldt-Jakob disease with Alzheimer-type A beta-reactive amyloid plaques, Histoparhology, 26, 445 - 450.

Barger, S. W, Horster, D., Furukawa, K., Goodman, Y., Krieglstein, J. & Mattson, M. P. (1995) Tumor necrosis factor-a and p protect neurons against amyloid P-peptide toxicity: evidence for involvement of kappa B-binding factor and attenuation of peroxide and Ca2 ’ accumulation, Proceeding of the National Academic Sciences USA, 92, 9328 - 9332.

Barger, S. W. & Van Eldik, L. J. (1992). SlOOP stimulates calcium fluxes in glial and neuronal cells, Journal of Biological Chemistry, 267, 9689-9694.

Bauer, J., Strauss, S., Schreiter-Gasser, U., Genter, U., Schlegel, P., Witt, I . : Yolk, B. & Berger, M. (1991) Interleukin-6 and a-2-macroglobulin indicate an acute-phase state in Alzheimer’s disease cortex, FEBS Letters, 285, 1 I 1 - 114.

Beck, E. & Daniel, P. M. (1969). Degenerative disease of the central nervous System transmissible to experimental animals, Postgraduate Medical Journal, 45, 361 - 370.

Behan, P. 0. & Feldman, R. G. (1970) Serum proteins, amyloid and Alzheimer’s disease. Journal of American Geriatric Society, 18, 792 - 797.

Berg, L., McKeel, D. W. Jr., Miller, J. P., Baty, J. & Morris, J . C. (1993) Neuropdtho~ogicd~ indexes of Alzheimer’s disease in demented and nondemented persons aged 80 years and older, Archives of Neurology, 50, 349- 358.

Bernstein, H. G., Bruszis, S., Schmidt, D., Wiederanders, B. & Dorn, A. (1989) Immunodetec- tion of cathepsin D in neuritic plaques found in brains of patients with dementia of Alzheimer type. Journal fGr Hirnforschung, 30, 613 --618.

Bessler, H., Sirota, P., Hart, J. & Djaldetti, M. (1989) Lymphokine production in patients with Alzheimer’s disease, Age Ageing, 18, 21 -25.

Blalock, J. E. (1989) A molecular basis for bidirectional communication between the immune and neuroendocrine systems, Physiology Reviews, 69, 1 - 32.

Blass, J. P. & Gibson, G. E. (1991) The role of oxidative abnormalities in the pathophys~ology of Alzheimer’s disease, Revue Neurologique, 147, 51 3 - 525.

ogy, 28, 83-88.

84, 259-263.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

IMMUNOLOGY A N D INFLAMMATION IN ALZHEIMERS DISEASE 225

Blass, J. P., KO, L. & Wisniewski, H. M. (1991) Pathology of Alzheimer‘s disease, Psychiatric Clinics of North America, 14, 397-420.

Bondareff, W., Mountjoy, C. Q. & Roth, M . (1982) Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia, Neurologji, 32,

Bongioanni, P., Romano, M. R., Sposito, R., Castagna, M., Boccardi. B. & Borgna, M. (1997) T-cell tumour necrosis factor-alpha receptor binding in demented patients, Journal of Neurology, 244, 418-425.

Bowen, D. M. (1981) Alzheimer’s disease. In: Davison, A. N. & Thompson, R. H. S. (Eds.), Chapter 24. The molecular basis of neuropathology (pp. 649- 665). London: Edward

164- 168.

Arnold Ltd. Breitner. J. C. S.. Gau, B. A,. Welsh, K. A,. Plassman, B. L.. McDonald, W. M., Helms, M. J. &

Anthony, J . C. ( 1 994) Inverse association of anti-inflammatory treatments and Alzheimer’s disease: initial results of a co-twin control study, Neurology, 44. 227 -232.

Breitner, J. C. S., Welsh, K. A, , Helms, M. J., Gaskell, P. C., Gau, B. A,, Roses, A. D., Pericak- Vance, M. A. & Saunders, A. M. (1995) Delayed onset of Alzheimer’s disease with nonsteroidal anti-inflammatory and histamine-Hi, blocking drugs. Neurobiology of Aging, 16, 523- 530.

Breitner, J. C. S. (1996) Inflammatory processes and antiinflammatory drugs in Alzheimer’s disease: A current appraisal, Neurobiology of Aging, 17, 789-794.

Bristow, C. L. & Boackle, R. J. (1986) Evidence for the binding of human serum amyloid P component to C1, and Fab gamma, Molecular Immunology, 23, 1045- 1052.

Burnet, F. M. (1970) An immunological approach to ageing, Lancet, i i , 358-360. Businaro, R., Fabrizi. C., Persichini, T., Starace, G., Ennas, M. G., Fumagalli, L. & Lauro, G.

M. (1997) Modulation of the alpha 2 macroglobulin receptorilow density lipoprotein receptor related protein by interferon-gamma in human astroglial cells, Journal of Neuroimmunology, 72, 75 - 8 1.

Cacabelos, R., Barquero, M., Garcia, P., Alvarez, X. A. & Vareva de Seijas, E. (1991) Cerebrospinal fluid interleukin-10 (IL-13) in Alzheimer’s disease and neurological disorders, Melhods and Findings in Experimental and Clinical Pliarmacology. 13, 455 - 458.

Card, P. J., Meade. R. P. & Davis, L. G. (1988) Immunocytochemical localization of the precursor protein for 0-amyloid in the rat central nervous system, h‘ruron, 1, 835-846.

Castalio, E. M . & Frangione, B. (1988) Biology of disease, Human amyloidosis, Alzheimer disease and related disorders, Laborarory fnvestigaliun, 58, I22 - 132.

Cataldo, A. M., Barnett, J. L., Berman, S. A., Li. J. H., Quarless, S., Bursztajn, S., Lippa, C. & Nixon, R. A. (1995) Gene expression and cellular content of cathepsin D in Alzheimer’s disease brain: evidence for early up-regulation of the endosomal-lysosomal system, Neuron. 14, 671 -680.

Chapman, J., Bachar. O., Korczyn, A., Wertman, E. & Michaelson, D. M. (1988) Antibodies to cholinergic neurons in Alzheimer’s disease, Journal of Neurochrmistry, 51, 479 -485.

Chen. S. , Frederickson, R. C. & Brunden, K. R. (1996) Neuroglial-mediated immunoin- flammatory responses in Alzheimer’s disease: complement activation and therapeutic approaches, Neurobiology of Aging, 17, 78 I - 787.

Cherkaoui, J., Mayo, W., Neveu, P. J . , Kelley, K. W., Vitiello, S., Le Moal, M. & Simon, H. (1990) The nucleus basalis is involved in brain modulation of the immune system in rats. Brain Research, 516, 345- 348.

Choi-Miura, N.-H. & Oda, T. (1996) Relationship Between Multifunctional Protein “Clusterin” and Alzheimer Disease, Neurohiolo,v of’ Aging, 17. 717- 722.

Cohen, D. & Eisdorfer. D. (1980) Serum immunoglobulins and cognitive status in the elderly: 1. A population study, Brirish Journal of Psj,chiutry, 136, 33 -39.

Colon, E. J . (1973) The cerebral cortex in presenile dementia, A quantitative study, Acru N~~uropathologiccr (Berlin), 23, 28 1 - 290.

Coria, F., Rubio, I . & Bayon, C. (1994) Alzheimer’s disease, beta-amyloidosis, and aging. Revim in the .Veuro.sc~iences, 5, 275 - 292.

Cotman, C. W., Pike, C. J. & Copani, A. (1992) 3-amyloid neurotoxicity: a discussion of in vitro findings, Neurobiology of Aging, 13, 587- 590.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

226 M. POPOVIC et U I

Cotman, C. W., Tenner, A. J. & Cummings, B. J. (1996) /3-Amyloid Converts an Acute Phase Injury Response to Chronic Injury Responses, Neurobiology of Aging, 17, 723 - 731.

Coyle, J. T., Price, D. L. & DeLong, M. R. (1983) Alzheimer’s disease: a disorder of cortical cholinergic innervation, Science, 219, 1184- 1190.

Cross, R. J., Brooks, W. H., Roszman, T. L. & Markesbery, W. R. (1982) Hypothalamic immune interactions, Effect of hypophysectomy on neuroimmunomodulation, Journal of Neurological Science, 53, 557- 566.

Curcio, C. A. & Kemper, T. (1984) Nucleus raphe dorsalis in dementia of the Alzheimer type: neurofibrillary changes and neuronal packing density, Journal of Neuropathologji and Experimental Neurology, 43, 359- 368.

Das, S. & Potter, H. (1995) Expression of the Alzheimer amyloid-promoting factor antichymotrypsin is induced is human astrocytes by IL-1, Neuron, 14, 447-456.

Dickson, D. W., Crystal, H. A., Mattiace, L. A., Kress, Y., Schwagerl, A,, Davies, P., Yen, S. H. & Aronson, M. K. (1989) Identification of normal and pathological aging in prospectively studied nondemented elderly humans, Neurobiology of Aging, 13, 1 - 11.

Dickson, D. W., Sinicropi, S., Yen, S.-H., KO, L.-W., Mattiace, L. A,, Bucala, R. & Vlassara, H. (1996) Glycation and Microglial Reaction in Lesions of Alzheimer’s Disease. Neurobiology of Aging, 17, 733-743.

Dodd, P. R., Scott, H. L. & Westphalen, R. I. (1994) Excitotoxic mechanisms in the pathogenesis of dementia, Neurochemistry International, 25, 203 - 219.

Donoso, A. (1991) Tratamiento farmacol6gico de la enfermedad de Alzheimer, Revista Medicu de Chile, 119, 452-457.

Dresse, A,, Marechal, D., Scuvee-Moreau, J . & Seutin, V. (1994) Towards a pharmacological approach of Alzheimer’s disease based on the molecular biology of the amyloid precursor protein (APP). Life Sciences, 55, 2179-2187.

Du Yan, S., Zhu, H., Fu, J., Yan, S. F., Roher, A., Tourtellotte, W. W., Rajavashisth, T., Chen, X., Godnian, G. C., Stern, D. & Schmidt, A. M. (1997) Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage- colony stimulating factor: a proinflammatory pathway in Alzheimer disease, Proceeding of the National Academic Sciences USA, 94, 5296 - 5301.

Duong, T., Nikolaeva, M & Acton, P. J. (1997) C-reactive protein-like immunoreactivity in the neurofibrillary tangles of Alzheimer’s disease, Bruin Research, 749, I52 - 156.

Edgington, T. S. & Dalessio, D. J. (1970) The assessment by immunofluorescence methods of humoral and antimyelin antibodies in man, Journal of Immunology, 105, 248-255.

Eikelenboom, P. & Stam, F. C . (1982) Immunoglobulins and complement factors in senile plaques, An immunoperoxidase study, Acta Neuropathologica (Berlin), 51, 239- 242.

Eikelenboom, P., Hack, C. E., Rozemuller, J. M. & Stam, F. C. (1989) Complement activation in amyloid plaques in Alzheimer’s dementia, Virchows Archiv, B, Cell Pathology, 56, 259- 262.

Eikelenboom, P., Rozemuller, J. M., Kraal, G., Stam, F. C., McBride, P. A.,Bruce, M. E. & Fraser, H. (1991) Cerebral amyloid plaques in Alzheimer’s disease but not in scrapie- affected mice are closely associated with a local inflammatory process, Virchows Archiv, B, Cell Pathology, 60, 329- 336.

Eikelenboom, P., Zhan, S.-S., van Gool, W. A. & Allsop, D. (1994) Inflammatory mechanisms in Alzheimer’s disease, Trends in Pharmacological Sciences, 15, 447 - 450.

Eikelenboom, P. & Veerhuis, R. (1996) The Role of Complement and Activated Microglia in the Pathogenesis of Alzheimer’s Disease, Neurobiology of Aging, 17, 673 - 680.

Eisdorfer, C. & Cohen, D. (1980) Serum immunoglobulines and cognitive status in the elderly: 2. An immunological-behavioral relationship? British Journal of Psychiatry, 136, 40 -45.

Eizenberg, O., Faber-Elman, A., Lotan, M . & Schwartz, M. (1995) Interleukin-2 transcripts in human and rodent brains- possible expression by astrocytes, Journal of Neurochamisfry. 64, 1928-1936.

Esumi, E., Araga, S. & Takahashi, K. (1991) Serum interleukin-2 in patients with dementia of the Alzheimer type, Acta Neurologica Scandinavica, 84, 65 - 67.

Fauman, M. A. (1982) The central nervous system and the immune system, Biological Psychiatry, 17, 1459- 1482.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


Felsenfeld, 0. & Wolf, R. H . (1972) Relationship of age and serum immunoglobulines to autoantibodies against brain constituents in primates, IA study in apparently healthy man, Macaca mulatta and Erythrolebus patas, Journal of Medical PrimatologJl, 1, 287- 296.

Ferrer, I., Alcantara, S., Ballabriga, J., Olive, M., Blanco, R., Rivera, R., Carmona, M., Berruezo, M., Pitarch, S. & Planas, A. M. (1996) Transforming growth factor-alpha (TGF- alpha) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain, Progress in Neurobiology, 49, 99 - 123.

Fillit, H. M., Kemeny, E., Luine, V., Weksler, M. E. & Zabrieskie, J . B. (1987) Antivascular antibodies in the sera of patients with senile dementia of the Alzheimer’s type, Journatfor Gerontology, 42, 180- 184.

Fillit, H., Luine, V. N., Reisberg, B., Amador, R., McEwen, B. &Zabriskie, J. B. (1985) Studies of the specificity of antibrian antibodies in Alzheimer’s disease. In: Hutton, J . T. & Kenney, A. D. (Eds.), Senile Dementia of the Alzheimer’s type, Neurology and Neurobiology, (pp. 307-318). New York: Alan R. Liss.

Finch, C . E. & Marchalonis, J. J. (1996) Evolutionary Perspectives on Amyloid and Inflammatory Features of Alzheimer Disease. Neurobiology of Aging, 17, 809 - 81 5.

Foley, P., Bradford, H . F., Docherty, M., Fillit, H., Luine, V. N., McEwen, B., Bucht, G., Winblad, B. & Hardy, J. (1988) Evidence for the presence of antibodies to cholinergic neurons in the serum of patients with Alzheimer’s disease, Journal of Neurology, 235,466 - 471.

Frei, K., Malipiero, U. V., Leist, T. P., Zinkernagel, R. M., Schwab, M . E. & Fontana, A. (1989) On the cellular source and function of interleukin-6 produced in the central nervous system in viral disease, European Journal of Immunology, 19, 689 - 694.

Frolich, L. & Riederer. P. (1995) Free radical mechanisms in dementia of Alzheimer type and the potential for antioxidative treatment, Arzneimirtelforschung, 45, 443 -446.

Fudenberg, H. H., Whitten, H. D., Arnaud, P. & Khansari, N. (1984) Is Alzheimer’s disease an immunological disorder? - observations and speculations, Clinical Immunology and Immunopathology, 32, 127- 131.

Gadient, R. A. & Otten, U. H. (1997) Interleukin-6 (IL-6)-a molecule with both beneficial and destructive potentials, Progress in Neurobiology, 52, 379- 390.

Ganter, U., Strauss, S., Jonas, U., Weidemann. A., Beyreuther, K., Volk, B., Berger, M. & Bauer, J . (1991) Alpha 2-macroglobulin synthesis in interleukin-6-stimulated human neuronal (SH-SYSY neuroblastoma) cells. Potential significance for the processing of Alzheimer beta-amyloid precursor protein, FEBS Letcem, 282, I27 - 131.

Gautrin, D. & Gauthier, S. (1989) Alzheimer’s disease: environmental factors and etiologic hypotheses, The Canadiun Journal qf Neurological Sciences, 16, 375 - 387.

Gebicke-Haerter, P. J . , Appel, K., Taylor, G. D., Schobert, A,, Rich, 1. N., Northoff, H . & Berger, M. ( 1 994) Rat microglia interleukin-3, Journal of Neuroimmunology, 50, 203 - 21 4.

Gehrmann, J . , Matsumoto, Y. & Kreutzberg, G. W. (1995) Microglia: intrinsic immunoeffector cell of the brain, Brim Research Reviews. 20. 269-287.

Genovesi, G., Paolini, P., Marcellini, L., Vernillo, E., Salvati, G., Polidori. G., Ricciardi, D., de Nuccio, I . & Re. M. (1996) Relationship between autoimmune thyroid disease Rand Alzheimer’s disease, Panminervu Medica, 38. 6 1 - 63.

Giacobini, E. (1 994) Therapy of Alzheimer disease: symptomatic or neuroprotective? Journal oJ Neural Transmission (Suppl) , 43, 2 I 1 - 2 1 7 .

Giulian, D. (1987) Ameboid microglia as effectors of inflammation in the central nervous system, Journal of Neuroscience Research. 18, 155- 171.

Giulian, D., Haverkamp, L. J., Yu, J . H., Karshin, W., Tom, D., Li, J., Kirkpatrick, J . , Kuo, L.-M. & Roher, A. E. (1996) Specific domains of P-amyloid from Alzheimer plaque elicit neuron killing in human microglia, Journal of Neuroscience, 16, 6021 - 6037.

Glenner, G. G. ( I 980) Amyloid deposits and amyloidosis- The $-fibrilloses. New Englund Journal of Medicine, 302, 1283- 1285.

Gottfries, C. G. (1994) Therapy options in Alzheimer’s disease, British Journal of Clinical Practice, 48, 327 ~~ 330.

Hamos, J . E., DeGennaro, L. J . & Drachman, D. A . (1989) Synaptic loss in Alzheimer’s disease and other dementias, Neurology, 39, 355 - 36 1.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

228 M. POPOVIC ei al.

Hanisch, U.-K. & Quirion, R. (1996) Interleukin-2 as a neuroregularoty cytokine, Brain

Henschke, P. J., Bell, D. A. & Cape, R. D. T. (1979) Immunologic indices in Alzheimer’s

Hermann, C., Stern, R. G., Losonzcy, M. F., Jaff, S. & Davidson, M. (1991) Diagnostic and

Herzog, A. G. & Kemper, T. L. (1980) Amygdaloid changes in aging and dementia, Archives of

Hind, C. R. K. (1986) Amyloidosis and Amyloid P Component, Wiley, New York. Ikeda, T., Yamamoto, K. , Takahashi, K. & Yamada, M. (1991a) Immune system-associated

antigens on the surface of peripheral blood lymphocytes in patients with Alzheimer’s disease. Acta Psychiatrica Scandinavica, 83, 444-448.

Ikeda, T., Yamamoto, K., Takahashi, K., Kaneyuki, K. & Yamada, M. (1991b) Interleukin-2 receptor in peripheral blood lymphocytes of Alzheimer’s disease patients. Acta Psychiatrica Scandinavica, 84, 262 -265.

Ingram, C. R., Phegan, K. J. & Blumenthal, H. T. (1974) Significance of an aging-linked neuron binding gamma globulin fraction of human sera, Journal of Gerontology, 29, 20- 27.

Ishii, T. & Haga, S. (1975) Identification of components of immunoglobulins in senile plaques by means of fluorescent antibody techniques, Acta Neuropafhologica (Berlin), 32, 157- 162.

Ishii, T. & Haga, S. (1976) Immuno-electron -microscopic localization of immunoglobulins in amyloid fibrils of sensile plaques, Acta Neuropathologica (Berlin), 36, 243 - 249.

Ishii, T. & Haga, S. (1984) Immuno-electron-microscopic localization of complements in amyloid fibrils of senile plaques, Acia Neuropathologica (Berlin), 63, 296 - 300.

Ishii, T., Haga, S. & Kametani, F. (1988) Presence of immunoglobulins and complements in the amyloid plaques in the brain of patients with Alzheimer’s disease. In: Pouplard-Barthelaix, A., Emile, J. & Christen, Y . (Eds.), Immunology and Alzheimer’s Disease (pp. 17-29), Berlin Heidelberg: Springer-Verlag.

Itagaki, S. , McGeer, P. L., Akiyama, H., Zhu, S . & Selkoe, D. J. (1989) Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease, Journal 01 Neuroimmunology, 24, 173- 182.

Jane, F. (1995) Tratamiento farmacologico de la enfermedad de Alzheimer: situation actual ,v perspectivas, Revista de Neurologia, 23, 103- 107.

JankoviC, B. D. & Spector, N. H. (1986) Effects on the immune system of lesioning and stimulation of the nervous system: neuroimmunomodulation. In: Plotnikoff, N. P., Faith, R. E., Murgo, A. J. & Good, R. A. (Eds.). Enkephalins and Endorphins. Stress and the Immune System (pp.189-220), New York: Plenum Press.

Jankovid, B. D., MarkoviC, B. M. & Spector, N. H. (Eds.) (1987) Neuroimmune interactions, (The New York Academy of Sciences, New York).

Jankovid, B. D., Jovanova-NeSid, K. & MarkoviC, B. M. (1988) Neuroimmunomodulation: potentiation of delayed hypersensitivity and antibody production by chronic electrical stimulation of the rat brain, International Journal of Neuroscience, 39, 153- 164.

Jenkinson, M . L., Bliss, M. R., Brain, A. T. & Scott, D. L. (1989) Rheumatoid arthritis and senile dementia of the Alzheimer’s type, British Journal of Rheumatology, 26, 86- 88.

Jiang, H., Burdick, D., Glabe, C. G., Cotman, C. W. & Tenner, A. J. (1994) P-Amyloid activates complement by binding to a specific region of the collagen-like domain of the Clq A chain, Journal of Immunology, 152, 5050 - 5059.

Joachim, C. L., Mori, H. & Selkoe, D. J . (1989) Amyloid @protein deposition in tissues other than brain in Alzheimer’s disease, Nature, 341, 226-230.

Johnson, S. A., Lampert-Etchells, M., Pasinetti, G. M., Rozovsky, I . & Finch, C. E. (1992) Complement mRNA in the mammalian brain: responses to Alzheimer’s disease and experimental brain lesioning, Neurobiology of Aging, 13, 641 - 648.

Jones, A. W. R. & Richardson, J . S. (1990) Alzheimer’s disease: clinical and pathological characteristics, International Jnzrrnal of Neuroscinre, 50, 147 - 168.

Jonker, C., Eikelenboom, P. & Tavenier, P. (1982) Immunological indices in the cerebrospinal fluid of patients with presenile dementia of the Alzheimer’s type, British Journal of Psychiatry, 140, 44-49.

Research Reviews, 21, 246 - 284.

disease, Journal of Clinical and Experimental Gerontology, 1, 23 - 21.

pharmacological approaches in Alzheimer’s, Drugs Aging, I , 144- 162.

Neurology, 37, 625 - 629.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

IMMUNOLOGY A N D INFLAMMATION IN ALZHEIMER’S DISEASE 229

Jovanova-NeSid, K., Nikolid, V. & Jankovid, B. D. (1993) Locus ceruieus and immunity. 11. Suppression of experimental allergic encephalomyelitis and hypersensitivity reactions in rats with lesioned locus ceruleus, International Journal of Neuroscience, 68, 289 -294.

Kalaria, R. N. (1992) The blood-brain barrier and cerebral microcirculation in Alzheimer’s disease, Cerebrovascular and Brain Metaholisn~ Reviews, 4, 226- 260.

Kalaria, R. N . (1993) Cerebral Microvasculature and Immunological Factors, Clinical Neuroscience, Al;heirnei:(’ Disease, 1, 204 - 2 1 1.

Kalaria, R. N., Golde, T. E., Cohen, M. L. & Younkin, S. G. (1991) Serum amyloid P in Alzheimer’s disease, Implications for dysfunction of the blood-brain barrier, Annals of the New York Academy of SL%iences, 640, 145 - 148.

Kalaria, R. N., Cohen, D . L. & Premkumar, D. R. (1996) Cellular aspects of the inflammatory response in Alzheimer’s disease, Neurodegeneration, 5, 497- 503.

Kalaria, R. N., Harshbarger-Kelly, M., Cohen. D. L. & Premkumar, D. R. D. (1996) Molecular Aspects of Inflammatory and Immune Response in Alzheimer‘s Disease, Neurobiology qf Aging, 17, 687-693.

Kalman, J., Juhasz, A,, Laird, G., Dickens. P., Jardanhazy, T., Rimanoczy, A., Boncz. I . . Parry-Jones, W. L. & Janka, 2. (1997) Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer’s disease, Acta Neuroiogira Scandinavica.

Kalter, S. & Kelly, S. (1975) Alzheimer’s disease, Evaluation of immunological indices, New York Stare Journal of Medicine, 75, 1222- 1225.

Kang, J. , Lemaire, H.-G., Unterbeck, A., Salbaum. J . M., Masters, C. L., Grzeschik, K.-H.. Multhaup, G. , Beyreuther, K. & Moller-Hill, 6. (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor, Nature, 325, 733 -736.

Khai, L. M., Kovalenkova. M. V., Korneva, E. A. & Seranova, A. E. (1964) Further study on the role of the hypothalamus region in the regulation of immunogenesis, Zurnal Mikrohiologii, Epichniohgii i lrnrnunologii. 41. 7 - 12.

Khansari, N., Whitten, H. D., Chou, Y . K. & Fudenberg, H . H. (1985) Immunological dysfunction in Alzheimer’s disease, Journal of Neuroirnmunologj~, 7 , 279 - 285.

Kingsley, B. S., Gaskin, F. & Fu, S. M. (1988) Human antibodies to neurofibrillary tangles and astrocytes in Akheimer’s disease, journal of lVeuroirnrnunology, 19. 89 - 99.

Kisilevsky, R. (1996) Anti-amyloid drugs: potential in the treatment of diseases associated with aging, Drugs Aging. 8, 75-83.

Klegeris, A., Walker. D. G. & McGeer, P. L. (1994) Activation of macrophages by Alzheimer d-amyloid peptide, Biochemical und Bioph,rsical Research Communications, 199, 984- 99 I .

Kornevd, E. A. & Khai. L. M. (1964) Effect of destruction of hypothalamic areas on immunogenesis. Fecleration Proceedings (Tvansl. Suppl.), 23, T88 -T92.

Kraus, L. J., Moss. M . B. & Rosene, D. L. (1985) Decreased natural killer cell activity in young adult basal forebrain damaged and normal aged. rhcsus monkeys. Society for NeuroscirncP Abstracts, 11, Part 2, 252.8.

Kumar, V. & Calache. M. (1991) Treatment of Abheimer’s disease with cholinergic drugs. International Journal C J ~ Clinical Phiirrnut~o/og>~. Therapy and To\-icology. 29, 23 - 37,

Lee, V. M.-Y & Trojanowski, J . Q. (1995) Tau proteins and their significance in the pathobiology of Alzheimer’s disease. In: Goate, A. & Ashall, F. (Eds.), Pathobiology of Alzheimer’s disease. (pp. 41 - 54), London: Academic Press Limited.

Leffell, M. S., Lumsden. L. & Steiger, W. A. (1985)An analysis o f T lymphocyte subpopulationsin patients with Alzheimer’s disease, Journal qf American Geriatric Societ?, 33, 4- 8.

Lemere, C. A.. Munger. J . S., Shi, G . P., Natkin. L., Haass, C., Chapman, H . A. & Selkoe, D. J . (1995) The lysosomal cysteine protease. cathepsin S, is increase in Alzheimer’s disease and Down syndrome brain: An immunocytochemical study, Ainrrican Journal qf’ Patlzolugy,

Leonardi, A., Arata. L.. Bino, G. , Caria. M . , Farinelli, M . , Parodi. C., Scudeletti, M. & Canonica, G. W. (1989) Functional study of T lymphocyte responsiveness in patient with dementia of the Alzheimer type, Journal of Ncuruinzniunolog?, 22. 19 - 22.

Lcrner, A., Cohen, D. L., Pax, A. B., Friedland, R. & Kalaria, R. N. (1993) Cell adhesion molecules in the vascular and neocortical pathology of Alzheimer‘s disease, Socier~. ,/or Neuroscience Abstracts, 19, 623.

96, 236-240.

146, 848- 860.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

230 M. POPOVIC et a(.

Lieberman, J., Schleissner, L., Techiki, K. H. & Kling, A. S. (1995) Serum alpha 1- antichymotrypsin level as a marker for Alzheimer-type dementia, Neurobiology of Aging,

Loeffler, D. A., Juneau, P. L., Nguyen, H. U., Najman, D., Pomara, N. & LeWitt, P. A. (1997) Immunocytochemical detection of anti-hippocampal antibodies in Alzheimer’s disease and normal cerebrospinal fluid, Neurochemical Research, 22, 209 - 214.

LOO, D. T., Copani, A., Pike, C. J., Whittemore, E. R., Walencewicz, A. J. & Cotman, C. W. (1993) Apoptosis is induced by P-amylid in cultured central nervous system neurons, Proceeding of the National Academic Sciences USA, 90, 7951 -1955.

Lopez, 0. L., Rabin, B. S. & Huff, F. J. (1991) Serum auto-antibodies in Alzheimer’s disease, Acla Neurologica Scandinavica, 84, 441 -444.

Lucca, U., Tettamanti, M., Foroloni, G. & Spagnoli, A. (1994) Nonsterodial anti-inflammatory drug use in Alzheimer’s disease, Biological Psychiatry, 36, 854- 856.

Lue, L. F., Brachova, L., Civin, W. H. & Rogers, J. (1996) Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer’s disease neurodegeneration, Journal of Neuropathology and Experimental Neurology, 55, 1083 - 1088.

Luo, Y. Q., Hirashima, N., Li, Y. H., Alkon, D. L., Sunderland, T., Etcheberrigaray, R. & Wolozin, B. (1995) Physiological levels of P-amyloid increase tyrosine phosphorylation and cytosolic calcium, Brain Research, 681, 65 - 74.

Ma, J., Brewer, H. B. Jr. and Potter, H. (1996) Alzheimer A beta neurotoxicity: promotion by antichymotrypsin, ApoE4; inhibition by A beta-related peptides, Neurobiology of Aging,

Macris, N. T., Schiavi, R. C., Camerino, M. S. & Stein, M. (1970) Effect of hypothalamic lesions on immune processes in the guinea pig, American Journal OfPhysiology, 219, 1205 - 1209.

Mann, D. M. A. & Yates, P. 0. (1986) Neurotransmitter deficit in Alzheimer’s disease and in other dementing disorders, Human Neurobiology, 5, 147- 158.

Marshak, D. R., Pesce, S. A., Stanley, L. C. & Griffin, W. S. T. (1992) Increased SlOOj9 neurotrophic activity in Alzheimer’s disease temporal lobe, Neurobiology of Aging, 13, 1 - 7.

Masliah, E., Terry, R. D., DeTeresa, R. & Hansen, L. A. (1989) Immunohistochemical quantification of the synapse-related protein synapthophysin in Alzheimer’s disease, Neuroscience Letters, 103, 234-239.

Masliah, E., Terry, R. D., Alford, M., DeTeresa, R. & Hansen, L. A. (1991) Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer’s disease, American Journal of Pathology, 138, 235-246.

Masliah, E., Mallory, M., Ge, N. & Saitoh, T. (1992) Protein kinases and growth associated proteins in plaque formation in Alzheimer’s disease, Reviews in the Neurosciences, 3, 99- 108.

Mattson, M. P., Tomaselli, K. J . & Rydel, R. E. (1993) Calcium-destabilizing and neurodegenerative effects of aggregated 0-amyloid peptide are attenuated by basic FGF, Brain Research, 621, 35-49.

May, P. C. & Finch, C. E. (1992) Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration, Trends in Neuroscience, 15, 391 - 396.

McGeer, P. L., Itagaki, S., Tago, H. & McGeer, E. G. (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR, Neuroscience Letters, 79, 195 - 200.

McGeer, P. L., Itagaki, S., Boyes, B. E. & McGeer, E. G. (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains, Neurology, 38, 1285- 1291.

McGeer, P. L., Akiyama, H., Itagaki, S. & McGeer, E. G. (1989a) Immune system response in Alzheimer’s disease, Canadian Journal of Neurological Science, 16, 5 16 - 527.

McGeer, P. L., Akiyama, H., Itagaki, S. & McGeer, E. G. (1989b) Activation of the classical complement pathway in brain tissue of Alzheimer’s patients, Neuroscience Letters, 197, 341 - 346.

McGeer, P. L., McGeer, E. G., Rogers, J. & Sibley, J. (1990) Anti-inflammatory drugs and Alzheimer disease, Lancet, 335, 1037.

16, 747-753.

17, 773 - 780.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


McGeer, P. L., McGeer, E. G., Kawamata, T.: Yamada, T. & Akiyama, H. (1991a) Reactions of the immune system in chronic degenerative neurological diseases, Canadian Journal of Neurological Sciences, 18, 376- 379.

McGeer, P. L., Walker, D. G., Akiyama, H., Kawamata, T., Guan, A., Parker, C. J . , Okada, N. & McGeer, E. G. (1991b) Detection of the membrane inhibitor of reactive lysis (CD59) in diseased neurons of Alzheimer brain, Brain Research, 5 4 , 315- 319.

McGeer, P. L., KaWamatd, T. & Walker. D. G. (1992a) Distribution of clusterin i n Alzheimer brain tissue, Brain Research, 579, 337- 341.

McGeer, P. L. & Rogers, J . (1992b) Anti-inflammatory agents as a therapeutic approach to Alzheimer’s disease, Neuroiogy, 42, 447 - 448.

McGeer, P. L., Schulzer, M. & McGeer, E. G. (1996) Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies, Neurology, 47, 425 - 432.

McKhann, G., Drachman, D., Flostein, M., Katzman, R., Price, D. & Stadlan, E. M. (1984) Clinical diagnosis of Alzheimer’s disease; report of the NINCDS-ADRDA Work group under the auspices of Department of Health and Human Services Task Force of Alzheimer’s disease, Neurology, 34, 939 -944.

McRae, A,, Ling, E. A., Polinsky, R., Gottfries, C. G. & Dahlstrom, A. (1991) Antibodies in the cerebrospinal fluid of some Alzheimer disease patients recognize amoeboid microglial cells in the developing rat central nervous system, Neuroscience, 41, 739 - 752.

McRae, A. & Dahlstrom, A. (1992) Immune responses in brains of Alzheimer’s and Parkinson’s disease patients: Hypothesis and reality, Reviews in the Neurosciences, 3, 79 -91.

McRae-Degueurce, A., Booj, S., Haglid, K., Rosengren, L., Karlsson, J. E., Karlsson, I . , Wallin, A,, Svennerholm, L., Gottfries, C. G. & Dahlstrom, A. (1987) Antibodies in the CSF of some Alzheimer’s patients recognize cholinergic neurons in the rodent central nervous system, Proceeding on the Nationai Academic Sciences USA, 84, 9214-9218.

McRae-Degueurce, A,, Haglid, K., Rosengren, L., Wallin, A,, Blennow, K., Gottfries, C. C. & Dahlstrom, A. (1988) Antibodies recognizing cholinergic neurons and thyroglobuline are found in the cerebrospinal fluid of a subgroup of patients with Alzheimer’s disease, Drug Development Research, 15, 153 - 163.

Michaelson, D. M., Chapman, J., Bachar, O., Korczyn, A. D. & Wertman, E. (1989) Serum antibodies to cholinergic neurons in Alzheimer’s disease, Progress in Clinical and Biological Research, 317, 689 - 694.

Miller, A. E., Neighbour, P. A., Katzman, R., Aronson, M. & Lipkowitz, R. (1981) Immunological studies in senile dementia of the Alzheimer type: evidence for enhanced suppressor cell activity, Annals of Neurology, 10, 506 - 510.

Moestrup, S. K., Gliemann, J. & Pallesen, G. (1992) Distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues, Cell and Tissue Research, 269, 375- 382.

Manning, U., Sandbrink, R., Weidemann, A., Banati, R. B., Masters, C. L. & Beyreuther, K. (1 995) Extracellular matrix influences the biogenesis of amyloid precursor protein in microglia cells, Journal of Biological Chemisiry, 270, 7104- 71 10.

Nakai, M., Kawamata, T., Taniguchi, T., Maeda, K. & Tanaka, C. (1996) Expression of apolipoprotein E mRNA in rat microglia, Neuroscience Letters, 211, 41 -44.

Nakajima, K. & Kohsaka, S . (1993) Functional roles of microglia in the brain, Neuroscience research, 17, 187 - 203.

Nandy, K. (1978) Brain-reactive antibodies in aging and senile dementia, In: Katzman, R., Terry, R. D. & Bick, K. L. (Eds.), Alzheimer’s Disease-Senile Dementia and Related Disorders, (pp. 198-205), New York: Raven Press.

Neveu, P. J . (1988) Cerebral neocortex modulation of immune functions, Life Sciences, 42, 191 7 - 1923.

Neveu, P. J . , Barnioud, P., Georgiades, O., Vitiello, S., Vincendeau, P. & Le Moal, M. (1989) Brain neocortex influence on the mononuclear phagocytic system, Journal of Neuroscience Research, 22, 188 - 193.

Nieto-Sampedro, M. & Berman, M. A. (1987) Interleukin-I-like activity in rat brain: sources, targets and effect of injury, Journal of Neuroscience Research, 17, 214-219.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

232 M . POPOVIC et a/.

Nieto-Sampedro, M. & Chandy, K. G. (1987) Interleukin-2-like activity in injured rat brain, Neurochemical Research, 12, 723 -727.

Nieto-Sampedro, M. & Mora, F. (1994) Active microglia, sick astroglia and Alzheimer type dementias, Neuroreport, 5, 375 - 380.

Nikolid, V., Jovanova-NeSiC, K. & Jankovid, B. D. (1993) Locus ceruleus and immunity. I . Suppression of plaque-forming cell response and antibody production in rats with lesioned locus ceruleus, International Journal of Neuroscience, 68, 283 - 287.

O’Banion, M. K. & Finch, C. E. (1996) Inflammatory Mechanisms and Anti-Inflammatory Therapy in Alzheimer’s Disease, Neurobiology 01’ Aging, 17, 666- 67 1.

Ogomori, K., Kitamoto, T., Tateishi, J., Sato, Y., Suetsaga, M. & Abe, M. (1989) 0-protein amyloid is widely distributed in the central nervous system of patients with Alzheimer’s disease, American Journal of Pathology, 134, 234-251.

Oltersdorf, T., Fritz, L. C., Schenk, D. B., Lieberburg, I., Johnson-Wood, K. L., Beattie, E. C., Ward, P. J., Blacher, R. W., Dovey, H. F. & Sinha, S. (1989) The secreted form of the Alzheimer’s amyloid precursor protein with the Kunitz domain is protease nexin-11. Nature, 341, 144-141.

Osmand, A. P., Friedenson, B., Gewurz, H., Painter, R. H., Hofman, T. & Shelton, E. (1977) Characterization of C-reactive protein and the complement subcomponent Clt as homologous proteins displaying cyclic pentameric symmetry (pentraxins), Proceeding of the National Academic Sciences U S A , 74, 139 - 143.

Ounanian, A,, Gilbert, B., Renversez, J. C., Seigneurin, J . M. & Avrameas, S. (1990) Antibodies to viral antigens, xeno antigens, and autoantigens in Alzheimer’s disease, Journal qf’ Clinical Laborntory Analysis, 4, 361-375.

Parnetti, L., Senin, U. & Mecocci, P. (1997) Cognitive enhancement therapy for Alzheimer’s disease, The way forward, Drugs, 53, 752 - 768.

Pasinetti, G. M. (1996) Inflammatory mechanisms in neurodegenerdtion and Alzheimer’s disease: The role of the complement system, Neurobiology of Aging, 17, 707-716.

Perlmutter, L. S. , Barf&, E., Saperia, D. & Chui, H. C. (1991) Association between vascular basement components and the lesions of Alzheimer’s disease, Journal of Neuroscience Research, 30, 673 - 681.

Perlmutter, L. S. , Scott, S. A., Barrbn, E. & Chui, H. C. (1992) Microglial association with senile plaques, extracellular neurofibrillary tangles and vascular amyloid, Neurohiology of Aging, 13(Supplelment I ) , S89.

Perry, E. K . & Perry. R. H. (1985) New insights into the nature of senile (Alzheimer-type) plaques, Trends in Neuroscience, 8, 301 - 303.

Perry, E. K., Tomlinson, B. E., Blessed, G., Perry, R. H., Cross, A. J . & Crow, T. J. (1981) Neuropathological and biochemical observations on the noradrenergic system in Alzheimer’s disease, Journal of Neurological Sceince, 51, 279 - 287.

Poliak, A. I., Rumbesht, L. M. & Sinichkin, A. A. (1969) Antibody synthesis following electrocoagulation of the posterior hypothalamic nucleus, Zurnal Microbiologii. Epidc- miologii i Immunologii, 46, 52 - 56.

Ponte, P., Gonzalez-DeWhitt, P., Schilling, J., Miller, J., Hsu, D., Greenberg, B., Davis, K.. Wallace, W., Lieberburg, I . , Fuller, F. & Cordell, B. (1988) A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors, Nature, 331, 525- 532.

Popovid, M., Jovanovd-NeSiC, K. & Popovid, N. (1995) Humoral and cellular immune responses in animal model of Alzheimer’s disease, Abstract hook of the International co- conference on Environmental Pollution ilCEP’95) and Neuroimmuno Interactions and Environment lICONE’951, St. Petersburg, Russia, 17---24 July, pp.161.

PopoviC, M., Jovanova-NeSid, K., Popovid, N., UgreSid, N., Kostid, V. & Rakid, Lj. (1997) Humoral and cell-mediated immune responses following lesions of the nucleus basalis magnocellularis in the rat, International Journal of Neuroscience, 89. 165- 176.

Powers, J . M. , Schlaepfer, W. W., Willingham, M. C. & Hall, B. J. (1981) An immunoperoxidase study of senile cerebral amyloidosis with pathogenetic considerations. Journal of Neuropathology and Experimental Neurology, 40, 592 - 612.

RadoSeviC-StaSiC, B., Cuk, M., MrakoviiC-SutiC, I., Trobonjaea, Z., Salamon, R., Stojanov, L.. Rukavina, D., Zupan, G. & Simonid, A. (1990) Immunological consequences of lesions of nucleus basalis in rats, International Journal of Neuroscience, 51, 325- 327.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


Raine, C. S., Cannella, B.. Dui.jvestijn, A. M. & Cross. A. H. (1990) Homing to central nervous system vasculature by antigen-specific lymphocytes, Lymphocyte/endothelial cell adhesion during the initial stages of autoimmune demyelination, Lahoratory inwsrigution, 63,476 - 489.

Rasool, C. G., Svendsen, C. N. & Selkoe. D . J . (1986) Neurofibrillary degeneration of cholinergic and noncholinergic neurons of the basal forebrain in Alzheimer’s disease, Annals of Neurology, 20, 482 -488.

Renoux, G., Biziere, K., Renoux, M. & Guillaumin. J . M . (1983) The production of T-cell- inducing factors in mice is controlled by the brain neocortex, Scandinavian Journal of Immunology, 17, 45 - 50.

Renoux, G., Biziere, K. , Renoux, M., Guillaumin. J. M. & Degenne, D. A. (1983) A balanced brain asymmetry modulates T-cell mediated events. Journal of Neuroinimunology, 5, 227 - 238.

Rich, J. B., Rasmusson. D. X., Folstein, M. F., Carson, K. A., Kawas, C. & Brandt, J . (1995) Nonsteroidal anti-inflammatory drugs in Alzheimer’s disease, Neurology, 45, 51 - 55.

Roberts, G. W., Lofthouse, R., Allsop, D., Landon. M., Kidd, M., Prusiner, S. B. & Crow, T. J. (1988) CNS amyloid proteins in neurodegenerative diseases, Neurology, 38, 1534 - 1540.

Rogers, J . , Brogan, D. & Mirra, S. S. (1985) The nucleus basalis of Meynert in neurological disease: a quantitative morphological study, Anizals of Neurology, 17. 163- 170.

Rogers, J . & Luber-Narod, J. (1988) Immune actions in the nervous system: A brief review with special emphasis on Alzheimer’s disease, Drug Development Research, 15, 227- 235.

Rogers, J., Luber-Narod. J., Styren, S. & Civin. W. H. (1988) Expression o f immune system- associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease, Neurobiology of Aging, 9, 339- 349.

Rogers, J., Cooper, N. R., Webster, S., Schultz, J . , McGeer, P. L., Styren, S. D., Civin, W. H., Brachova, L., Bradt, B., Ward, P. & Lieberburg, 1. (1992) Complement activation by [I- amyloid in Alzheimer’s disease, Proceeding of the National Academic Sciences USA, 89,

Rogers, J., Schultz, J., Brachova, L., Lue, L.-F., Webster, S., Bradt, B., Cooper, N. R. & Moss. D. E. ( 1 992) Complement activation and 5-amyloid-mediated neurotoxcity in Alzheimer’s disease, Research in Immunology, 143, 624- 630.

Rogers, J., Kirby, L. C., Hempelman, S. R., Berry, D. L., McGeer, P. L.. Kaszniak, A. W., Zdlinski, J., Cofield, M., Mansukhani, L., Wilson, P. & Kogan, F. (1993) Clinical trial of indomethacin in Alzheimer’s disease, Neurology.. 43, 1609- 161 I .

Rogers, J., Webster, S., Lue. L.-F., Brachova, L., Civin, W. H., Emmerling, M., Shivers, B., Walker, D. & McGeer, P. (1996) Inflammation and Alzheimer’s disease pathogenesis, Neuvohiology qf Aging, 17, 681 -686.

Rossi, F. & Bianchini, E. (1996) Synergistic induction of nitric oxide by :i-amyloid and cytokines in astrocytes, Biochemical and Biophj,sica6 Research Communications, 225, 474 - 478.

Saper, C. B., German. D. C. & White, C . L. 3rd (1985) Neuronal pathology in the nucleus basalis and associated cell groups in senile dementia of the Alzhimer’s type: possible role in cell loss, Neurology, 35, 1089- 1095.

Sawada, M., Suzumura, A. & Marunouchi, 7. (1995) Induction of interleukin-2 receptor in mouse microglia, Journal of Neurot.hemisrrj; 64, I973 - 1979.

Schmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B. J., Hulette, C. M., Jon, S. H., Pericak-Vance, M. A, , Goldgaber, D . & Roses, A. D. (1993) Increased amyloid fl-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease, Proceeding of the National Academic Sciences U S A , 90, 9649 - 9653.

1016- 1020.

Schnabel, J. (1993) New Alzheimer’s therapy suggested, Science, 260, 1719- 1720. Schott, K., Wormstall. H.. Dietrich, M., Klein, R. & Batra, A. (1996) Autoantibody reactivity

in serum of patients with Alzheimer’s disease and other age-related dementia, Psychiutrj. Research, 59, 251 -254.

Schwab, C., Steele, J. C . . McGeer, E. G. & McGeer. P. L. (1997) Amyloid P immunoreactivity precedes C4d deposition on extracellular neurofibrillary tangles. Acro Neuropahtologica (Berlin), 93. 87-92.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

234 M. POPOVIC et ai

Schwartz, 0. & Kurucz, A. (1965) Fluorescence microscopy demonstration of cerebrovascular and pancreatic insular amyloid in presenile and senile states, Journal of American Geriatric Society, 13, 199-205.

Shea, T. B. (1995) Role of glial-derived nexin in neuronal differentiation and in acute brain injury and potential involvement in exacerbation of neurodegeneration in Alzheimer’s disease, Brain Research Reviews, 20, 171 - 184.

Sheng, J. G., Mrak, R. E. & Griffin, W. S. (1995) Microglial interleukin-1 alpha expression in brain regions in Alzheimer’s disease: correlation with neuritic plaque distribution, Neuropathology and Applied Neurobiology, 21, 290 - 301.

Sheng, J. G., Ito, K., Skinner, R. D., Mark, R. E., Rovnaghi, C . R., Van Eldik, L. J . & Griffin, S. T. (1996) In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-I as a driving force in Alzheimer pathogenesis, Neurohiology ofAging, 17, 761 - 766.

Sims, N. R., Finegan, J. M. & Blass, J. P. (1987) Altered metabolic properties of cultured skin fibroblasts in Alzheimer’s disease, Annals of Neurology, 21, 451 - 457.

Singh, V. K. (1997) Neuroautoimmunity: pathogenic implications for Alzheimer’s disease, Gerontology, 43, 79 -94.

Singh, V. K. & Fudenberg, H. H. (1 986) Detection of brain autoantibodies in the serum ofpatients with Alzheimer’s disease but not with Down’s syndrome, Immunology Letters, 12,277-280.

Singh, V. K. & Fudenberg, H. H. (1989). Increase of immunoglobulin G3 subclass is related to brain autoantibody in Alzheimer’s disease but not in Down’s syndrome. Autoimmunity, 3,

Sisodia, S. S. & Price, D. L. (1993). Amyloidogenesis in Alzheimer’s Disease. Clinical Neuroscience, Alzheimer’s Disease, 1, 176- 183.

Skias, D., Bania, M., Reder, A. T., Luchins, D. & Antel, J. P. (1985). Senile dementia of Alzheimer’s (SDAT): reduced T8 + - cell-mediated suppressor activity. Neurology, 35,

Smith, R. P., Higuchi, D. A. & Broze, G. J.Jr. (1990). Platelet coagulation factor XI,-inhibitor. a form of Alzheimer amyloid precursor protein. Science, 248, 1126- 1128.

Smith, W. L., Borgeat, P. & Fitzpatrick, A. F. (1991). The eicosanoids cyclooxigenase, lipoxigenase, and epoxygenase pathways. In: Vance, D. E. & Vance, J. (Eds.), Biochemisty of lipids, lipoproteins and membranes, (pp. 297-325). New York: Elsevier.

Smith, W. L. & Marnett, L. J. (1991). Prostaglandin endoperoxide synthase: Structure and catalysis. Biochimika and Biphysica Acta, 1083, 1 - 17.

Solerte, S. B., Fioravanti, M., Severgnini, S., Pezza, N., Locatelli, M., Cerutti, N., Terenzi, F. & Ferrari, E. (1997). Excitatory pattern of gamma-interferon on natural killer cell activity in senile dementia of the Alzheimer type. Dementia Geriatrica and Cognitive Disorders, 8,

Soll, A. H., Weinstein, W. M., Kurata, J. & McCarthy, D. (1991). Nonsteroidal anti- inflammatory drugs and peptic ulcer disease. Annals of Internal Medicine, 114, 307- 319.

Solomon, B., Koppel, R., Hanan, E. & Katzav, T. (1996). Monoclonal antibodies inhibit in vifro fibrillar aggregation of the Alzheimer beta-amlyoid peptide, Proceeding of the National Academic Sciences USA, 93, 452-455.

Sorbi, S., Piacentini, S. , Latorraca, S., Piersanti, P. & Amaducci, L. (1995). Alterations in metabolic properties in fibroblasts in Alzheimer disease, Alzheimer Disease and Associated Disorders, 9, 73 -77.

Stopa, E. G., Gonzalez, A. M., Chorsky, R., Corona, R. J., Alvarez, J., Bird, E. D. & Baird, A. (1990). Basic fibroblast growth factor in Alzheimer’s disease, Biochemical and Biophysical Research Communications, 171, 690- 696.

Strittmater, W. J . , Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak- Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D. & Roses, A. D. (1993). Binding of human apolipoprotein E to synthetic amyloid /3 peptide: isoform-specific effects and implications for lateonset Alzheimer disease. Proceeding of the National Academic Sciences

Sunami, A. & Tasaka, K. (1991). Two aspects of the excitatory influence of histamine on hippocampal neurons in guinea pigs. Methods and Findings in Experimental and Clinical Pharmacology, 13, 85-91.

95-101.

1635- 1638.

308- 313.

USA, 90, 8098-8102.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


Tagliavini, F., Giaccone. G . Frangione, R. & Bugiani. 0. (1988). Preamyloid dcposits in the cerebal cortex of patients with Alzheimer‘b disease and nondemented individuals. Nruroscicnce I x t t r r s . 93, 19 I - 196.

Tanaka, J., Nakamura. K., Takeda, M., Tada. K.. Suzuki, H., Morita, H . . Okado, S., Hariguchi, T. & Nishimura, T. ( 1 989). Enzyme-linked immunosorbent assay for human autoantibody to glial fibrillary acidic protein: higher titer of the antibody is detected in serum of pateints with Alzheimer’s disease. Acra Neruologicu Scundina~ku, 80, 554- 560.

Tavolato, B. & Argentiero. V. (1980). Immunological indices in presenile Alzheimer’s disease. Journal of Neurological Sciiwct., 46, 325 - 33 1.

Tennent, G. A., Lovat, L. B. & Pepys, M. B. (3995). Serum amyloid P component prevents proteolysis of the amyloid librils of Alzhemicr disease and systemic amyloidosis, Procrrding of rlie Nurional Acudemic science^ L‘SA. 92, 4299 -4303.

Terry. R. D. & Peck, A.. DeTeresa, R.. Schechter. R. & Horoupian, D. S. (1981). Some morphometric aspects of the brain in sensile dementia of the Alzheimer type. Annul.$ o/ NwroloLqy, 10, 184 192.

Thorpc, S. R . & Baynes. J . W. (1996). Role of the Maillard reaction in diabetes mellitus and diseases of aging. Drcrgs Agina, 9, 69 ~ 77.

Togashi, S.. Lim, S. K., Kawano. H., Ito, S., Ishihara. T., Okada, Y., Nakano, S., Kinoshita, T., Horie, K . , Episkopou, V., Gotlesman, M. E.. Costantini, F., Shimada. K . & Maeda, S. (1997). Serum amyloid P component enhances induction of murine amyloidosis. Luhorutory Inrestigution, 77, 525- 53 1 .

Tomlinson, B. E., Irving, D. & Blessed, G. (1981). Cell loss in the locus coeruleus in senile dementia of Alzheimer type. Journal of Naurologiczl Science, 49, 41 9 - 428.

Tooyama. I . , Kawamata. T . Akiyama, H., Moestriip. S. K . , Gliemann. J . & McCeer, P. L. (1993). lmmunohistochemical study of alpha 2 macroglobulin receptor in Alzheimer and control postmorten human brain. Moliwlar. rind C‘ltemicul Neurophntliolog~.. 18. 153 - 160.

Tyrey, L. & Nalbandov. A. V. (1972). Influence of anterior hypothalamic lesions on circulating antibody titers in the rate. Ainerican Jourriul of’P/ij..siolo~y, 222, 179 - 185.

Vandenabcclc, P. & Fiers, W. (1991). Is amyloidogenesis during Alzheimer‘s disease due to an IL-I-:IL-6 mediated ‘acute phase rcsponse’ in the brain. Imr~n~nologl. Torlcr).. 12, 217-219.

Van der Wal, E. A,, G6me7-Pinilla, F. & Cotman. C. W. (1993). TrdnSfOrming growth,factor- beta I is in plaques in Aliheirner and Down pathologies. Neurorcyort. 4. 69--72.

Van Cool, D., De Stroopcr. B . . Van Leuven, F.. Triau. E. & Dom, R. (1993). a2-Macroglobulin expression in neuritic-type plaques in patients with Alzheimer’s disease. .\’czrohiohgy of Agif7g, 14, 233-237.

Van Nostrand, W. E.. Wagner. S. L., Suzuki, M.. Choi. B. H., Farrow. J . S.. Gcddes, J . W.. Cotman, C. W. & Cunningham, D. D . (1989). Protease nexin. I . I . , a potent antichymotrypsin, shows identity to amyloid .$protein precursor. Nutzrre. 341. 546- 549.

Vane. J . & Botting. R. (1987). Inflammation and the mechanism of action of anti-inflammatory drugs. FASER h l I 1 ’ 1 7 ~ 4 l , 1. 89-96.

Vane. J. (1994). Towards a better aspirin. Narrrrr. 367. 215 216. Veerhuis, R., Janssen. 1.. Hack. C. E. & Eikelcnboom. P (1996). Early complement components

Verbeek, M. M., Otte-Holler. 1.. Westphal, J . R.. Wesseling, P., Ruiter, 0. J. & de Waal, R. M. in Alzheimer’s disease brains. Actu Ncuroparhologica (Berlin), 91, 53 -60.

(I 994). Accumulation o f intraccllular adhesion molccule-l in senile plaques in brain tissue o f patients with Alrheirncr‘s disease. Afmvicot7 Jorrrnnl o f P u t h o / o , ~ , ~ ~ , 144. 104

VLtjkovii.. S., Nikolid, V.. Nikolid, A, , Milanovid. S. & Jankovid, B. D. (1994). Asymmetrical modulation of immune reactivity in left- and right-biased rats after ipsilateral ablation of the prefrontal, parietal and occipital brain neocortex. lnrernu/ionul .Journal of”Yauro. 78. 123-134.

Wagner. S. L., Geddes. J . W.. Cotman, C. W., Lau. A. L., Gurwitr. D.. Isackson. P. J . & Cunningham, D. I). (1989). Protease ncxin-I. an antithrombin with neurite outgrowth activity, is reduced in Alzheimcr disease. Proweclifig of’ ~ h r Nutioncrl Acrro‘cwiic Scicvice.s CSA. 86, 8284 - 8288.

Wolkcr, D. G. & McGeei-. P . L. (1992). Compleii~ent gene expression in human brain: comparison bctween normal and Alzheimer discase cases. Molec~crlur Bruit7 Ru.srurc,h, 14. 109 116.

I 16.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.


Walker, D. G., Yasuhara, O., Patston, P. A., McGeer, E. G. & McGeer, P. L. (1995). Complement C1 inhibitor is produced by brain tissue and is cleaved in Alzheimer disease. Brain Research, 675, 75 - 82.

Watts, H. F. (1985). Investigations into an immunological component in Alzheimer’s disease. Interdisciplinary Topics in Gerontology, 19, 54-61.

Watts, H., Kennedy, P. G. E. & Thomas, M. (1981). The significance of anti-neuronal antibodies in Alzheimer’s disease. Journal of Neuroimmunology, 1, 107- 116.

Webster, S., Bonnell, B. & Rogers, J. (1997). Charge-based binding of complement component Clq to the Alzheimer amyloid beta-peptide. American Journal of Pathology, 150, 1531 - 1536.

Wenk, H. (1989). The nucleus basalis magnocellularis Meynert (NBmM) complex-a central integrator of coded “limbic signals” linked to neocortical modular operation? A proposed (heuristic) model of function. Journal fur Hirnoforschung, 30, 127- 151.

Whitehouse, P. J., Price, D. L., Struble, R. G., Clark, A. W., Coyle, J . T. & DeLong, M. R. (1982). Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science, 215, 1237- 1239.

Whitehouse, P. J. (1991). Treatment of Alzheimer disease. Alzheimer Disease and A.r.roriated Disorders, 5 (Suppl.l), S32-536.

Wood, J. A., Wood, P. L., Ryan, R., Graff-Radford, N. R., Pilapil, C., Robitaille, Y. & Quirion, R. (1993). Cytokine indices in Alzheimer’s temporal cortex: no changes in mature IL-la or IL-1RA but increases in the associated acute phase proteins IL-6, 02- macroglobulin and C-reactive protein. Brain Research, 629, 244-252.

Xu, S. & Gaskin, F. (1997). Increased incidence of anti-beta-amyloid autoantibodies secreted by Epstein-Barr virus transformed B cell lines from patients with Alzheimer’s disease. Mechanisms of Ageing and Development, 94. 213 -222.

Yamada, T., Tsubouchi, H., Daikuhara, Y., Prat, M., Comoglio, P. M., McGeer, P. L. & McGeer, E. G. (1 994). Immunohistochemistry with antibodies to hepatocyte growth factor and its receptor protein (c-MET) in human brain tissues. Brain Research, 637, 308- 312.

Yamada, K., Kono, K., Umegaki, H., Yamada, K., Iguchi, A., Fukatsu, T., Nakashima, N., Nishiwaki, H., Shimada, Y., Sugita, Y., Yamamoto, T., Hasegawa, T. & Nabeshima, T. (1995). Decreased interleukin-6 level in the cerebrospinal fluid of patients with Alzheimer- type dementia. Neuroscience Letters, 186, 219- 221.

Yamada, T., Yoshiyama, Y., Tsuboi, Y. & Shimomurd, T. (1997). Astroglial expression of hepatocyte growth factor and hepatocyte growth factor activator in human brain tissues. Brain Research, 762, 251 -255.

Yamamoto, T. & Hirano, A. (1985). Nucleus raphe dorsalis in Alzheimer’s disease: neurofibrillary tangles and loss of large neurons. Annals of Neurology, 17, 573- 577.

Yanker, B. A,, Duffy, L. K. & Kirschner, D. A. (1990). Neurotrophic and neurotoxic effects of amyloid p protein: reversal by tachykinin neuropeptides. Science, 250, 279- 282.

Yanker, B. A. & Mesulam, M.-M. (1991). Pamyloid and the pathogenesis of Alzheimer’s disease. New England Journal of Medicine, 326, 1292-~ 1293.

Zubenko, G. S., Cohen, B. M., Boller, F., Malinakova, I., Keefe, N. & Chojndcki, 6. (1987). Platelet membrane abnormality in Alzheimer’s disease. Annals of Neurology, 22. 237 - 244.

Int J

Neu

rosc

i Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

McM

aste

r U

nive

rsity

on

11/1

7/14

For

pers

onal

use

onl

y.

Documents

Importance of Immunological and Inflammatory Processes in the Pathogenesis and THERAPY of Alzheimer's Disease