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ALZHEIMERS DISEASE

Erin Dancey


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Overview

Alzheimers is the most common cause ofdementia in adult life and is associated with theselective damage of brain regions and neuralcircuits critical for memory and cognition

The pathogenesis of this disease is complex, andinvolves 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

Alzheimers patients show numerous plaques which arecomposed of 4 kD Amyloid-beta (A-beta) peptides, whichare derived from beta amyloid precursor proteins (APPs)

APP is a membrane associated glycoprotein of 110-135kDa that is proposed to normally behave in the brain asa cell surface signaling molecule

A-beta peptides are generated in the endosomalcompartment and in the endoplasmic reticulum or golgicomplex by endoproteolytic cleavage of APP by Beta,alpha, and gamma secretases


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Presenilins

Presenilin 1 (PS1) and presenilin 2 (PS2) arehighly homologous 43-50 kD proteins with eighttransmembrane domains

Presenilins make crucial contributions toneurodegeneration in AD

Presenilins are crucial components of the

enzymes that work to cleave APP, and mutationsin presenilins cause the production of A-beta42and A-beta43 peptides (insoluble forms of A-beta)


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The production of A-beta

production by processing of APP


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Amyloid Plaque formation

About 90% of the secreted A-beta peptidesformed from processing of APP are A-beta40, a

soluble form of the peptide About 10% of secreted A-beta peptides are A-

beta42 and A-beta43

A-beta42 and A-beta43 are highly fibrillogenic,readily aggregated, and neurotoxic


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Alignment of the sequence of the42 residue peptide of the plaque of

Alzheimers disease


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Schematic representation of aparallel beta sheet in an amyloid

fibril


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Micrographs of amyloid fibrils


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Micrograph of amyloid fibres


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Neurofibrillary pathology

Intracellularly, alzheimers patients showneurofibrillary pathology

Affected neurons accumulate tau andubiquitin immunoreactivities withinneurofibrillary tangles, in cell bodies and

dendrites, and in dystrophic neuritis


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Plasmin

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

It has been hypothesized that brains of patientswith AD may have lower levels of plasmin

The higher production of amyloid peptidetogether with less efficient degradation would to

A-beta accumulation and aggregation


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Early Onset Alzheimers

Most cases of early onset AD are familialautosomal dominant disorders caused by

mutations in APP, PS1, and PS2Various substitutions have been studied

and they have found various mutations

that cause the individuals to secrete ahigher fraction of A-beta42 and/or A-beta43 peptides


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Late Onset Alzheimers

In late onset alzheimers, there are nospecific gene mutations that are

associated with the inheritance of thedisease

However, specific alleles of apoliprotein E4

(apoE) and alpha2 macroglobulin areassociated with increased risk ofalzheimers


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Amyloid Hypothesis

The trigger for alzheimers disease is the A-betapeptide, and the accumulation of this peptide inthe form of plaques is the initiating molecular

event The plaques trigger an inflammatory response,

neuronal cell death, and gradual cognitivedecline

The rest of the disease process, includingformation of neurofibrillary tangles containingtau protein, is caused by an imbalance between

A-beta production and A-beta clearance


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The sequence of pathogenic eventsleading to AD proposed by the

amyloid hypothesis


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Postulated evolution of structuralabnormalities and evidence of A-

beta deposits in the hippocampus


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Support for the Amyloid Hypothesis

The A-beta peptide is the primary component ofthe necrotic brain tissue

Mutations in the gene encoding the tau proteinscause frontotemporal dementia withparkinsonism

However, parkinsonism is characterized by

severe deposition of tau in neurofibril tangles inthe brain, but there is no deposition of amyloid


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Support for the Amyloid Hypothesis

Growing evidence indicates that geneticvariability in A-beta catabolism and

clearance may contribute to the risk oflate onset of AD


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Problems with the amyloid

hypothesis The number of amyloid deposits in the brain do not

correlate well with the degree of cognitive impairmentthat the patient experienced in life. In some cases,

individuals without symptoms of AD have many corticalA-beta deposits. However, in these cases, these arediffuse 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 onneuronal function have not been defined in vivo


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Problems with the amyloid

hypothesis Another concern is that the fact that all AD causing

mutations in APP, PS1, or PS2 increase A-betadeposition, yet the degree to which a particular mutationaffects A-beta production in cell culture shows no simplecorrelation with the age at which if first producessymptoms

The degree of dementia appears to correlate withsoluble A-beta species. Several lines of evidence haveconverged recently to demonstrate that soluble

oligomers of A-beta, instead of monomers or insolubleamyloid fibrils, may be responsible for synapticdysfunction in the brains of AD patients and in animalmodels


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Calcium Hypothesis

Calcium modulates many neural processes, includingsynaptic plasticity and apoptosis

Dysregulation of intracellular calcium signaling has been

implicated in the pathogenesis of alzheimers disease Increased intracellular calcium elicits the characteristic

lesions of this disorder, including the accumulation ofamyloid-beta, the hyperphosphorylation of TAU andneuronal death

Every gene that is known to increase susceptibility toAlzheimers disease also modulates some aspect ofcalcium signaling


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Calcium Hypothesis

The disruption of calcium homeostasismight be one of the principal mechanisms

by which A-beta manifests itsneurotoxicity

A-beta has been shown to destabilize

neuronal 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 the

observation 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 alower incidence of Alzheimers disease

5. Based on the observation that A-beta

aggregation is, in part, dependent on the metalions zinc and copper. This strategy reasons thatchelation of these ions in vivo may prevent A-beta deposition


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References

1. Price, D.L., Sisodia, S.S., and Borchelt, D.R. (1998). GeneticNeurodegenerative Diseases: The Human Illness and TransgenicModels. Science 282, 1079-1093

2. Vassar, R., and Bennet, B.D. (1998) Beta-secretase cleavage of

alzheimers amyloid precursor protein by the transmembraneaspartic protease BACE. Science 286, 5440-5464 3. LaFerla, F.M. (2002) Calcium dyshomeostasis and intracellular

signalling in alzheimers disease. Nature Reviews Neuroscience 3,862-872

4. Gregersen, N., Bross, P., and Andresen, B.S. (2001) The role of

chaperone-assisted folding and quality control in inborn errors ofmetabolism: Protein folding disorders. Journal of InheritedMetabolic Disorders 24, 189-212

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