Molecular Biology and Molecular Biology and Pathogenesis of Alzheimer’s Pathogenesis of Alzheimer’s DiseaseDiseaseAlexandre Henri-Bhargava, R4Neurology Academic Half-DayFeb. 20, 2009

By the end of this lecture By the end of this lecture you should...you should...

1. Be able to describe the major histopathological findings in Alzheimer’s disease

2. Describe (beta-amyloid) plaque formation and its possible role in the pathogenesis of AD

3. Describe neurofibrillary (tau) tangle formation and its possible role in the pathogenesis of AD

4. Know that other molecules likely have a role in the pathogenesis of AD

Lecture OutlineLecture OutlineIntroduction / History of ADMain histopathological findings in ADBeta-amyloid and its role in plaque

formation◦Evidence for amyloid in the

etiopathogenesis of ADTau and its role in neurofibrillary

tangle formation◦Evidence for tau in the etiopathogenesis of

ADOther molecules involved in AD

◦Very briefly!Concluding remarks

IntroductionIntroductionDementia with predominant

amnesiaMost common neurodegenerative

disorder◦> 70% of dementias

Incidence rises exponentially after age 65

The best cure would be prevention

HISTOPATHOLOGYHISTOPATHOLOGY

From Neurology in Clinical Practice, 5th ed.; 2008.

Senile plaquesSenile plaques

Drawing by Charles Yanofsky, MD

Diffuse plaque

Senile plaque

WHAT FORMS WHAT FORMS PLAQUES?PLAQUES?

Beta-amyloidBeta-amyloidDiscovered as the product at the

core of the “miliary substance” in 1984

Formed by sequential cleavage of the APP gene product

Two main isoforms: Aβ42 and Aβ40◦Aβ42 usually forms < 10% of total,

but is perhaps more toxic

Amyloidogenic pathway

Non-amyloidogenic pathway

APP

““DEPOSITION OF DEPOSITION OF AMYLOID PLAQUES IS AMYLOID PLAQUES IS THE CAUSATIVE AGENT THE CAUSATIVE AGENT OF ALZHEIMER OF ALZHEIMER PATHOLOGY”PATHOLOGY”

Support for the Support for the ββAptistsAptistsAutosomal dominant forms of AD

◦48 families with 18 mutations in APP◦PSEN1 (240 families) and PSEN2 (16

families) Both gene products are part of the

gamma-secretase complex

Support for the Support for the ββAptistsAptistsAutosomal dominant forms of ADTrisomy 21 all develop AD-like

pathology◦APP gene is on chromosome 21◦Increased copy # of APP gene is

sufficient to cause increased serum amyloid

Support for the Support for the ββAptistsAptistsAutosomal dominant forms of ADTrisomy 21 all develop AD-like

pathologyApoE4 +/+ have increased Aβ42

deposition in their brains◦ApoE4 is the only known

susceptibility gene for AD

Support for the Support for the ββAptistsAptistsAutosomal dominant forms of ADTrisomy 21 all develop AD-like

pathologyApoE4 +/+ have increased Aβ42

deposition in their brainsElevated Aβ concentrations found

in presymptomatic individuals

Support for the Support for the ββAptistsAptistsAutosomal dominant forms of ADTrisomy 21 all develop AD-like

pathologyApoE4 +/+ have increased Aβ42

deposition in their brainsElevated Aβ concentrations found

in presymptomatic individualsPlaque # correlates with disease

burden

Support for the Support for the ββAptistsAptistsAutosomal dominant forms of ADTrisomy 21 all develop AD-like pathologyApoE4 +/+ have increased Aβ42

deposition in their brainsElevated Aβ concentrations found in

presymptomatic individualsPlaque # correlates with disease burdenRats that overexpress Aβ can have

cognitive deficits reversed by antibodies directed against Aβ oligomers

WHAT FORMS WHAT FORMS TANGLES?TANGLES?

TauTauMAP (microtubule-associated protein)Product of MAPT gene, 6 splice

variantsStabilizes microtubules Regulates axonal

transportFunction highly

regulated by kinase-mediatedphosphorylation

TauTau

TauTau

In tauopathies, such as AD, tau metabolism is dysregulated, resulting in increased unbound (free) tau, which can form cytotoxic agglomerations

““DYSEQUILIBRIUM OF DYSEQUILIBRIUM OF TAU FUNCTION IS THE TAU FUNCTION IS THE INITIATING EVENT FOR INITIATING EVENT FOR ALZHEIMER ALZHEIMER PATHOLOGY”PATHOLOGY”

Support for the TauistsSupport for the TauistsAnatomical distribution of tangle

(tau) pathology is better correlated with AD◦entorhinal cortex (ERC) ->

hippocampus -> temporal neocortex -> other association cortices

◦follows CNS areas involved in clinical progression of AD In contradistinction to the

topographical distribution of neuritic plaques

Support for the TauistsSupport for the TauistsAnatomical distribution of tangle

(tau) pathology is better correlated with AD

tau mutation by itself is sufficient to cause a neurodegenerative illness◦FTDP-17 is caused my a mutation in

MAPT gene

Support for the TauistsSupport for the TauistsAnatomical distribution of tangle

(tau) pathology is better correlated with AD

tau mutation by itself is sufficient to cause a neurodegenerative illness

Some persons with extensive plaque formation are not demented

Support for the TauistsSupport for the TauistsAnatomical distribution of tangle

(tau) pathology is better correlated with AD

tau mutation by itself is sufficient to cause a neurodegenerative illness

Some persons with extensive plaque formation are not demented

GSK3, a tau kinase, also processes Aβ◦Links tau to plaque pathology◦Tau as an "upstream" mediator of

amyloid toxicity

OTHER MOLECULES OTHER MOLECULES INVOLVED IN INVOLVED IN PATHOGENESIS OF PATHOGENESIS OF ADAD

Synners, Heretics, and Synners, Heretics, and UnitariansUnitariansalpha-synuclein desposits in non-

amyloid component of neuritic plaques

Role of inflammatory mediators◦What are those microglia doing?◦ROS and RNS

Calcium signallingLipidsBasal cholinergic forebrain-

specificity?Microenergy depletion

Agnostics and AtheistsAgnostics and AtheistsIS AD one single disease or a

phenotype of multiple diseases?Does AD exist as a disease or is it

simply “accelerated ageing” of the brain?

ConclusionConclusionOriginal pathological description

of AD 100 years ago: plaques and tangles

Plaques = beta-amyloid + other molecules◦Inflammatory component

Tangles = tauOther molecules are likely

involved in pathogenesis of AD

Take-home pointsTake-home pointsProponents of amyloid hypothesis

propose targeting therapies at beta- and gamma-secretases, Aβ42 molecules

Proponents of tau propose targeting proteins involved in tau signalling

Other scientists are implicating other molecules to target, therapeutically

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