Molecular Biology and Pathogenesis of Alzheimer’s Disease Alexandre Henri-Bhargava, R4 Neurology Academic Half-Day Feb. 20, 2009

By the end of this lecture you should 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 Outline Introduction / History of AD Main histopathological findings in AD Beta-amyloid and its role in plaque formation ◦ Evidence for amyloid in the etiopathogenesis of AD Tau and its role in neurofibrillary tangle formation ◦ Evidence for tau in the etiopathogenesis of AD Other molecules involved in AD ◦ Very briefly! Concluding remarks

Introduction Dementia with predominant amnesia Most common neurodegenerative disorder ◦ > 70% of dementias Incidence rises exponentially after age 65 The best cure would be prevention

HISTOPATHOLOGY

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

Senile plaques Drawing by Charles Yanofsky, MD Diffuse plaque Senile plaque

WHAT FORMS PLAQUES?

Beta-amyloid Discovered as the product at the core of the “miliary substance” in 1984 Formed by sequential cleavage of the APP gene product Two main isoforms: A β 42 and A β 40 ◦ A β 42 usually forms < 10% of total, but is perhaps more toxic

Amyloidogenic pathway Non-amyloidogenic pathway APP

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

Support for the β Aptists Autosomal 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 β Aptists Autosomal dominant forms of AD Trisomy 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 β Aptists Autosomal dominant forms of AD Trisomy 21 all develop AD-like pathology ApoE4 +/+ have increased A β 42 deposition in their brains ◦ ApoE4 is the only known susceptibility gene for AD

Support for the β Aptists Autosomal dominant forms of AD Trisomy 21 all develop AD-like pathology ApoE4 +/+ have increased A β 42 deposition in their brains Elevated A β concentrations found in presymptomatic individuals

Support for the β Aptists Autosomal dominant forms of AD Trisomy 21 all develop AD-like pathology ApoE4 +/+ have increased A β 42 deposition in their brains Elevated A β concentrations found in presymptomatic individuals Plaque # correlates with disease burden

Support for the β Aptists Autosomal dominant forms of AD Trisomy 21 all develop AD-like pathology ApoE4 +/+ have increased A β 42 deposition in their brains Elevated A β concentrations found in presymptomatic individuals Plaque # correlates with disease burden Rats that overexpress A β can have cognitive deficits reversed by antibodies directed against A β oligomers

WHAT FORMS TANGLES?

Tau MAP (microtubule-associated protein) Product of MAPT gene, 6 splice variants Stabilizes microtubules Regulates axonal transport Function highly regulated by kinase- mediated phosphorylation

Tau

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

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

Support for the Tauists Anatomical 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 Tauists Anatomical 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 Tauists Anatomical 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 Tauists Anatomical 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 A β ◦ Links tau to plaque pathology ◦ Tau as an "upstream" mediator of amyloid toxicity

OTHER MOLECULES INVOLVED IN PATHOGENESIS OF AD

Synners, Heretics, and Unitarians alpha-synuclein desposits in non-amyloid component of neuritic plaques Role of inflammatory mediators ◦ What are those microglia doing? ◦ ROS and RNS Calcium signalling Lipids Basal cholinergic forebrain-specificity? Microenergy depletion

Agnostics and Atheists IS 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?

Conclusion Original pathological description of AD 100 years ago: plaques and tangles Plaques = beta-amyloid + other molecules ◦ Inflammatory component Tangles = tau Other molecules are likely involved in pathogenesis of AD

Take-home points Proponents of amyloid hypothesis propose targeting therapies at beta- and gamma-secretases, A β 42 molecules Proponents of tau propose targeting proteins involved in tau signalling Other scientists are implicating other molecules to target, therapeutically

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