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LZHEIMER’S
DISE SE
PRESEENTED BY
ARUN VARUGHESE
GROUP -7
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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
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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
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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
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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
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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)
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THE PRODUCTION OF A-BETA
PRODUCTION BY PROCESSING OF APP
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Alignment of the sequence of the 42
residue peptide of the plaque of
Alzheimer’s disease
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Schematic representation of a
parallel beta sheet in anamyloid fibril
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Micrographs of amyloid
fibrils
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Micrograph of amyloid fibres
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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
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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.
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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
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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.
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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.
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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.
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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
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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
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The sequence of pathogenic
events leading to AD proposed
by the amyloid hypothesis
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Postulated evolution of
structural abnormalities andevidence of A-beta deposits in
the hippocampus
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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
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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
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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
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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
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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
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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
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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
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THANK YOU
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