AD ARUN

8/10/2019 AD ARUN

http://slidepdf.com/reader/full/ad-arun 1/33

LZHEIMER’S

DISE SE

PRESEENTED BY

ARUN VARUGHESE

GROUP -7

8/10/2019 AD ARUN


OVERVIEW

Alzheimer’s is the most common cause ofdementia in adult life and is associated with theselective damage of brain regions and neural

circuits critical for memory and cognition The pathogenesis of this disease is complex, and

involves many molecular, cellular, andphysiological pathologies

The neurons in the neocortex, hippocampus,amygdala, and the basal forebrain cholinergicsystem are the most affected brain regions

8/10/2019 AD ARUN


8/10/2019 AD ARUN


8/10/2019 AD ARUN


AMYLOID PLAQUE FORMATION

Alzheimer’s patients show numerous plaques which arecomposed of 4 kD Amyloid-beta (A-beta) peptides, which arederived from beta amyloid precursor proteins (APPs)

APP is a membrane associated glycoprotein of 110-135 kDa thatis proposed to normally behave in the brain as a cell surfacesignaling molecule

A-beta peptides are generated in the endosomal compartmentand in the endoplasmic reticulum or golgi complex byendoproteolytic cleavage of APP by Beta, alpha, and gammasecretases

8/10/2019 AD ARUN


About 90% of the secreted A-beta

peptides formed from processing of APP are A-beta40, a soluble form ofthe peptide

About 10% of secreted A-betapeptides are A-beta42 and A-beta43

A-beta42 and A-beta43 are highlyfibrillogenic, readily aggregated, and

neurotoxic

8/10/2019 AD ARUN


Alignment of several strands of

A-beta show that A-beta42 and A-beta43 preferentially form

networks of salt linkages andstrong hydrogen bonds betweenionized side chains of opposite

charge which thus form theobserved plaques

8/10/2019 AD ARUN


PRESENILINS

Presenilin 1 (PS1) and presenilin 2 (PS2) are highlyhomologous 43-50 kD proteins with eight transmembranedomains

Presenilin’s make crucial contributions toneurodegeneration in AD

Presenilin’s are crucial components of the enzymes thatwork to cleave APP, and mutations in presenilins cause theproduction of A-beta42 and A-beta43 peptides (insolubleforms of A-beta)

8/10/2019 AD ARUN


THE PRODUCTION OF A-BETA

PRODUCTION BY PROCESSING OF APP

8/10/2019 AD ARUN


Alignment of the sequence of the 42

residue peptide of the plaque of

Alzheimer’s disease

8/10/2019 AD ARUN


Schematic representation of a

parallel beta sheet in anamyloid fibril

8/10/2019 AD ARUN


Micrographs of amyloid

fibrils

8/10/2019 AD ARUN


Micrograph of amyloid fibres

8/10/2019 AD ARUN


EARLY ONSET OF ALZHEIMERS

Most cases of early onset AD are familialautosomal dominant disorders caused bymutations in APP, PS1, and PS2

Various substitutions have been studied andthey have found various mutations that cause

the individuals to secrete a higher fraction ofA-beta42 and/or A-beta43 peptides

8/10/2019 AD ARUN


Individuals with early-onset Alzheimer's disease will

exhibit many of the same symptoms as those whose

disease appears later in life. Forgetfulness, confusion,difficulty completing simple tasks, problems with

communication and personality changes are among the

possible experiences that may be encountered. Anyone

who has this combination of symptoms should see aphysician as soon as possible.

Alzheimer's diagnosis usually comes as a result of ruling

out all other possibilities. The only way to biologicallydiagnose it is to examine brain tissue under a

microscope, which is typically done only after death.

http://alzheimers.about.com/od/symptomsofalzheimers/a/symptoms.htm

http://alzheimers.about.com/od/diagnosisofalzheimers/a/diagnosis.htm

http://alzheimers.about.com/od/diagnosisofalzheimers/a/diagnosis.htm

http://alzheimers.about.com/od/symptomsofalzheimers/a/symptoms.htm

8/10/2019 AD ARUN


8/10/2019 AD ARUN


LATE ONSET OF ALZHEIMERS

In late onset alzheimer’s, there are no specific

gene mutations that are associated with theinheritance of the disease

However, specific alleles of apoliprotein E4(apoE) and alpha2 macroglobulin areassociated with increased risk of alzheimers

8/10/2019 AD ARUN


Late- onset Alzheimer’s disease is the most common form of the illnessaffecting about 90% of sufferers. It only occurs in people over the age of 65. And alarmingly it appears to affect around 50% of all people over the age

of 85.

Late-onset Alzheimer's is also known as “sporadic Alzheimer’s” becausethere appears to be no genetic factor or family link involved. Late onset Alzheimer’s causes memory loss, confusion and difficulties in carrying out

even the simplest tasks. Eventually a person will need constant care as theywill be unable to look after themselves.On average people live roughly eightto ten years after diagnosis.

Sometimes with sporadic Alzheimer’s, because it affects people so late inlife, another disease associated with old age could also be the cause ofdeath. Apolipoprotein E (ApoE) is found on chromosone 19. The e4 type ofthe gene is found to carry a higher risk of Alzheimer’s while the e2 type isbelieved to offer protection against it.

8/10/2019 AD ARUN


8/10/2019 AD ARUN


The 2 primary cardinal lesions associated with Alzheimer's disease are theneurofibrillary tangle and the senile plaque. The neurofibrillary tangle consistsof abnormal accumulations of abnormally phosphorylated tau within theperikaryal cytoplasm of certain neurons. The senile plaque consists of a central

core of beta-amyloid, a 4-kD peptide, surrounded by abnormally configuredneuronal processes or neurites. Other neuropathological lesions areencountered in cases of Alzheimer's disease, but the disease is defined andrecognized by these 2 cardinal lesions.

Other lesions include poorly understood changes such as granulovacuolardegeneration and eosinophilic rodlike bodies (Hirano bodies). The loss ofsynaptic components is a change that clearly has a significant impact oncognitive function and represents another important morphological alteration. Itis important to recognize that distinguishing between Alzheimer's disease,

especially in its early stages, and normal aging may be very difficult,particularly if one is examining the brains of patients who died at an advancedold age.

8/10/2019 AD ARUN


PATHOGENS OF ALZHEIMERS

Alzheimer's disease damages and kills brain cells.Two types of brain cell (neuron) damage are commonin people who have Alzheimer's:

-Plaques. Clumps of a normally harmless proteincalled beta-amyloid may interfere withcommunication between brain cells.-Tangles. The internal support structure for brain cellsdepends on the normal functioning of a proteincalled tau. In people with Alzheimer's, threads of tauprotein undergo alterations that cause them to

become twisted,causing them to die.

8/10/2019 AD ARUN


PLASMIN

In the brain, plasminogen and its proteolyticfragment are abundant in the hippocampus

It has been hypothesized that brains of patients

with AD may have lower levels of plasmin

The higher production of amyloid peptide

together with less efficient degradation would to

A-beta accumulation and aggregation

8/10/2019 AD ARUN


AMYLOID HYPOTHESIS

The trigger for alzheimer’s disease is the A-betapeptide, and the accumulation of this peptide inthe form of plaques is the initiating molecularevent

The plaques trigger an inflammatory response,neuronal cell death, and gradual cognitivedecline

The rest of the disease process, including

formation of neurofibrillary tangles containingtau protein, is caused by an imbalance betweenA-beta production and A-beta clearance

8/10/2019 AD ARUN


The sequence of pathogenic

events leading to AD proposed

by the amyloid hypothesis

8/10/2019 AD ARUN


Postulated evolution of

structural abnormalities andevidence of A-beta deposits in

the hippocampus

8/10/2019 AD ARUN


SUPPORT FOR THE AMYLOID

HYPOTHESIS The A-beta peptide is the primary component of the

necrotic brain tissue

Mutations in the gene encoding the tau proteins cause

frontotemporal dementia with parkinsonism However, parkinsonism is characterized by severe

deposition of tau in neurofibril tangles in the brain, butthere is no deposition of amyloid

Growing evidence indicates that genetic variability in A-

beta catabolism and clearance may contribute to the riskof late onset of AD

8/10/2019 AD ARUN


PROBLEMS WITH AMYLOID

HYPOTHESIS

The number of amyloid deposits in the brain do not correlate wellwith the degree of cognitive impairment that the patientexperienced in life. In some cases, individuals without symptoms ofAD have many cortical A-beta deposits. However, in these cases,these are diffuse amyloid plaques that are not associated withsurrounding necrotic and glial pathology

The amyloid hypothesis remains controversial because a specific

neurotoxic species of A-beta and its effects on neuronal functionhave not been defined in vivo

8/10/2019 AD ARUN


Another concern is that the fact that all ADcausing mutations in APP, PS1, or PS2 increase A-

beta deposition, yet the degree to which aparticular mutation affects A-beta production in cellculture shows no simple correlation with the age atwhich if first produces symptoms

The degree of dementia appears to correlate withsoluble A-beta species. Several lines of evidencehave converged recently to demonstrate that

soluble oligomers of A-beta, instead of monomersor insoluble amyloid fibrils, may be responsible forsynaptic dysfunction in the brains of AD patientsand in animal models

8/10/2019 AD ARUN


CALCIUM HYPOTHESIS

Calcium modulates many neural processes, including synapticplasticity and apoptosis

Dysregulation of intracellular calcium signaling has beenimplicated in the pathogenesis of alzheimer’s disease

Increased intracellular calcium elicits the characteristic lesions ofthis disorder, including the accumulation of amyloid-beta, thehyperphosphorylation of TAU and neuronal death

Every gene that is known to increase susceptibility to Alzheimer’sdisease also modulates some aspect of calcium signaling

8/10/2019 AD ARUN


The disruption of calcium homeostasis

might be one of the principal mechanismsby which A-beta manifests itsneurotoxicity

A-beta has been shown to destabilizeneuronal calcium homeostasis, generallyleading to an increase in cytosolic calciumwhich can then trigger neuronal apoptosis

8/10/2019 AD ARUN


TREATMENT STRATEGIES

1. One could attempt to partially inhibit proteases thatgenerate A-beta from APP

2. One could attempt to prevent the oligomerization ofA-beta or enhance clearance from the cerebral cortex

3. An anti-inflammatory strategy based on theobservation that a cellular inflammatory response in thecerebral cortex is elicited by the progressiveaccumulation of A-beta

8/10/2019 AD ARUN


TREATMENT STRATEGIES

4. Based on modulating cholesterolhomeostasis. Chronic use of cholesterollowering drugs have been associated with a

lower incidence of Alzheimer’s disease

5. Based on the observation that A-betaaggregation is, in part, dependent on the metal

ions zinc and copper. This strategy reasons thatchelation of these ions in vivo may prevent A-beta deposition

8/10/2019 AD ARUN


THANK YOU

Documents

AD ARUN