Transcript Molecular Biology and Pathogenesis of Alzheimer’s Disease

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...
1.
2.
3.
4.
Be able to describe the major
histopathological findings in Alzheimer’s
disease
Describe (beta-amyloid) plaque formation and
its possible role in the pathogenesis of AD
Describe neurofibrillary (tau) tangle formation
and its possible role in the pathogenesis of AD
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, 5th ed.; 2008.
Senile plaques
Diffuse
plaque
Senile
plaque
Drawing by Charles Yanofsky, MD
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: Aβ42 and Aβ40

◦ Aβ42 usually forms < 10% of total, but is
perhaps more toxic
Non-amyloidogenic pathway
APP
Amyloidogenic pathway
“DEPOSITION OF
AMYLOID PLAQUES IS
THE CAUSATIVE AGENT
OF ALZHEIMER
PATHOLOGY”
Support for the βAptists

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 gammasecretase complex
Support for the βAptists
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 βAptists
Autosomal dominant forms of AD
 Trisomy 21 all develop AD-like pathology
 ApoE4 +/+ have increased Aβ42
deposition in their brains

◦ ApoE4 is the only known susceptibility gene
for AD
Support for the βAptists
Autosomal dominant forms of AD
 Trisomy 21 all develop AD-like pathology
 ApoE4 +/+ have increased Aβ42
deposition in their brains
 Elevated Aβ concentrations found in
presymptomatic individuals

Support for the βAptists
Autosomal dominant forms of AD
 Trisomy 21 all develop AD-like pathology
 ApoE4 +/+ have increased Aβ42
deposition in their brains
 Elevated Aβ concentrations found in
presymptomatic individuals
 Plaque # correlates with disease burden

Support for the βAptists
Autosomal dominant forms of AD
 Trisomy 21 all develop AD-like pathology
 ApoE4 +/+ have increased Aβ42 deposition
in their brains
 Elevated Aβ concentrations found in
presymptomatic individuals
 Plaque # correlates with disease burden
 Rats that overexpress Aβ can have cognitive
deficits reversed by antibodies directed
against Aβ 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 kinasemediated
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 Aβ

◦ 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, Aβ42 molecules
 Proponents of tau propose targeting
proteins involved in tau signalling
 Other scientists are implicating other
molecules to target, therapeutically

References
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