Download Alzheimer`s disease

Aging in the CNS
Normal age-related changes
Overall reduction in brain weight (20%)
Narrowing of gyri
Widening of sulci
Dilation of the ventricles
Widening of the subarachnoid space
Results from:
Atrophy of large neurons
Regression of dendritic tree
Reduction in dendritic spines
Loss of myelin
Leads to:
Mild to moderate memory impairments
Neuronal atrophy
No generalized loss of neurons, rather atrophy of large, selectively vulnerable
neurons:
Pyramidal neurons in the entorhinal and neocortices
Pyramidal neurons in the CA1 and CA2 regions of the hippocampus
Vulnerability:
Large neurons
High energy requirements
Large cell surface for exposure
to toxic conditions.
Rhesus monkey
Cortical pyramidal neuron
Dendritic atrophy
- Reduced dendritic tree complexity
- Decreased spine density
- Decreased excitatory input since
excitatory synapses occur on spines
- Decreased synaptic plasticity and
sprouting
Dendritic spines
Myelination increase most rapidly during first five
years of life, but continues into the 5th decade.
Demyelination/remyelination is always ongoing, but in
later life, demyelination outpaces remyelination.
Ratio of gray to white matter is 1:28 in the young
brain, declines to 1:13 by 7th decade.
Total brain myelin content
Loss of myelin
Primary pathology of oligodendrocytes, not
secondary to neuronal dysfunction.
Bartzokis, et al., 2008. Neurobiol. Aging.
Myelin loss is most evident
in the anterior regions of the brain
Genu
Splenium
Splenium
Total brain myelin content
Genu
Head, D.,et al., 2004, Cerebral Cortex, 14:410
Bartzokis, et al., 2008. Neurobiol. Aging.
Loss of myelin correlates with
cognitive impairment
Peters, A. 2002. J. Neurocytol., 31:581-593
Accumulation of pigments and oxidation products
• Lipofuscin – Lipofuscin is a pigment which accumulates primarily
within neuronal cell bodies; composed of lipid-containing
residues formed by oxidative degradation in lysosomes.
• Oxidation products – Oxidative modification of DNA, proteins and lipids.
Reactive oxygen species (e.g., hydroxyl radicals) inactivate enzymes
and alter proteins leading to abnormal accumulation and aggregation.
Exacerbated by malfunction in the proteosome and lysosomal
degradative pathways.
Pathological aging
Genetic or environmental factors alter or accelerate
underlying mechanisms of normal brain aging
Results in accelerated loss of neurons
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Normal
Normal aged
Alzheimer’s disease
Estimated 5.3 million Americans have AD
Half of all demented patients have AD
Alzheimer’s
Impairments in memory, problem solving,
judgment, visual-spatial perception,
sometimes hallucinations and delusions.
Generalized shrinkage of the cortex and
hippocampus; neuronal loss in those
areas.
CT scans
Normal
AD
Alzheimer’s disease
Neuronal loss in areas of high cognition
and memory:
Neocortex (frontal and parietal)
Entorhinal cortex
Hippocampus
Nucleus basalis (of Meynert)
Normal
Alzheimer’s
Normal
Thangavel, et al., Neuroscience, 154:667, 2008.
Alzheimer’s
http://library.med.utah.edu
Pathologies of protein aggregation
NFTs
Senile (amyloid) plaques (SP)
Aggregated beta amyloid protein
Neurofibrillary tangles (NFT)
Aggregated tau protein
SPs
Silver stain
Occur in very low numbers in
normal, aged brain; prominent in
Alzheimer’s disease in areas
where neuronal loss occurs
Senile plaques
(Amyloid plaques)
Dystrophic
processes
Extracellular, spherical structures
Senile plaques consist of a core of betaamyloid protein surrounded by
degenerated neuronal processes,
reactive astrocytes and microglia
Senile plaques are most commonly found in
the cerebral cortex and hippocampus
Beta amyloid
Senile plaque
Plaques mature and enlarge as beta-amyloid protein
aggregates
The senile plaques are an end-stage cytopathology
Diffuse plaque
Mature plaque
Imaging Alzheimer’s disease
Previously, definitive diagnosis required
autopsy findings of senile plaques
Pittsburg Compound-B (PIB)
Crosses blood brain barrier
Binds to amyloid core in the plaque
PET imaging
fluorodeoxyglucose
Klunk, WE et al., 2004. Ann. Neurol., 55(3): 306.
The severity of AD dementia
does not necessarily correlate
with “plaque-load”.
Mathis, et al., 2007. Nucl. Med. Biol.,34:809.
The majority of human gene mutations linked to early Alzheimer’s disease onset
either involve the APP protein or the cleavage enzymes.
Neurofibrillary tangles (NFTs)
Large, intracellular, flame shaped
masses of abnormal filaments in the
cell body and base of large dendrites.
Prominent in large neurons in the
hippocampus, the entorhinal cortex
and other neocortical sites.
Composed of abnormally hyperphosphorylated tau in helically
wound filaments.
H&E
Silver
Progression of neuropathology in normal
aging and Alzheimer’s disease: a continuum?
Normal young
No pathologies
Normal aging
Plaques in cortex and hippocampus
NFT’s in entorhinal cortex
Mild cognitive impairment
Plaques and tangles increased
Mild neuronal loss in entorhinal cortex
Alzheimer’s disease
Plaques and tangles highly increased
Widespread neuronal cell loss
Extent of both correlate with dementia
Yankner, et al., Annu. Rev. Pathol. Mech. Dis., 3:41, 2008.
The amyloid theory
of Alzheimer’s disease pathogenesis
Nucleus basalis (of Meynert)
http://library.med.utah.edu
Major cholinergic input to the cortex, neuromodulatory action.
Pharmacological basis for the main FDA approved treatment of AD, inhibitors of
acetylcholinesterase (Aricept)
Cognitive function declines as the levels of acetylcholine (ACh) decline due to the
loss of neurons in the basal forebrain. By inhibiting the breakdown of the
remaining ACh by AChE, cognition is improved.