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Ageing block > Neuropathology of AD > Flashcards

Neuropathology of AD Flashcards

1
Q

Outline the characteristics of AD

A
  • more common in women
  • only 50% receive a clinical diagnosis
  • progressive synpatic, neuronal loss leads to brain atrophy
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2
Q

Outline the role of genetics in AD

A

-Late onset(LOAD)>65yrs-common ‘sporadic’, although high heritability (60-80%)
-Early onset <65 -rare;
largely familial, autosomal dominant
-APOE gene variants contribute the most to genetic risk
-APOE4 = highest risk
-APOE2= protective
-APOE genes are insufficient to predict diagnosis

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3
Q

Outline familial disease in AD

A

Mutations in 3 genes

  • amyloid precursor protein(APP), chr21
  • Presenilin 1 (PSEN-1), chr 14(most common)
  • Presenilin 2 (PSEN-2), chr 1
  • Sufficient to predict diagnosis
  • Tell us a lot about AD pathology/causes of disease
  • protein products of all 3 genes are involved in APP processing
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4
Q

Outline the histopathological diagnosis of AD

A
  1. )Plaques: extracellular Abeta(1-42) amyloid depositions (also in walls of the blood vessels), dystrophic neurites, activated microglia
  2. )Neurofibrillarly tangles: intracellular,acetylated paired helical filaments of hyperphosphorylated tau
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5
Q

What is the function of tau protein

A

-Proteins that stabilize micro-tubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.

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6
Q

How can amyloid& tau be monitored

A

in vivo

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7
Q

Outline other core progressive pathologies in AD

A
  • synaptic dysfunction
  • neuron loss
  • reactive gliosis
  • reactive microgliosis
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8
Q

What is gliosis ?

A

-Nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes.

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9
Q

Outline the neurodegenerative diseases characterised by protein aggregates &dysfunctional dying neurons

A
  1. )PD -lewy bodies of alpha synuclein
  2. ) HD- Huntingtin
  3. )AD-extracellular amyloid( alpha beta 1-42); intracellular P tau
  4. )Spinal and bulbar muscular atrophy androgen receptor
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10
Q

Outline activated microglia in AD

A
  • Microglia surrounds plaques, NFTs and damaged neurons
  • Change morphology-ramified to amoeboid
  • Increase in number-proliferation
  • Correlate with disease markers-neuronal cell death and emergence of behavioural symptoms
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11
Q

Outline the neuropathology of AD

A
  1. )Diffuse cortical and hippocampal atrophy
  2. )Progressive neuronal cell loss:
    - entorhinal cortex (located in the medial temporal lobe)
    - Hippocampus (located in the medial temporal lobe)
    - Basal forebrain
  3. )Aggregates:
    - Amyloid(senile)plaques
    - Neurofibrillary tangles
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12
Q

Where is shrinkage of gyri most likely to be seen in AD?

A

-In the temporal lobe (lower part of the brain) and frontal lobes (left part of the brain)

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13
Q

How may a PET scan showing glucose uptake be different in a healthy brain compared to that of an AD pt?

A
  • High levels of glucose upatke in a living healthy person
  • AD pts exhibits large decreases in energy metabolism in the frontal cortex (top of the brain) and temporal lobes(sides of the brain)
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14
Q

Amyloidogenic ABeta is generated as 2 peptides: Abeta(1-40) and Abeta(1-42). Which one is more prone to aggregation?

A

Abeta1-42

NB: APP(110-130kDA) is cleaved to release Abeta peptides of various lengths

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15
Q

What is the function of secretases

A

Act on the amyloid precursor protein (APP) to cleave the protein into three fragments

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16
Q

Outline the role of APP mutations in development of AD

A
  • Early onset,autosomal dominant
  • Largely missense mutations (N=13) (also gene duplication)
  • Affect ability of the secretases to cleave APP
17
Q

Outline Abeta peptides in AD

A
  • 2 major forms: Abeta1-40 and Abeta1-42
  • other minor forms: Abeta1-38,Abeta11-40,Abeta11-42, pE3-40/2
  • Abeta42 aggregates faster, seeds plaques and more neurotoxic
  • Many FAD mutations increase levels of Abeta40/42
  • Abeta 25-35 is non-physiological and has properties not shown by Abeta1-40 and 1-42
18
Q

Outline the characteristics of tau protein

A
  • MAPT gene on Chr 17
  • 6 isoforms in adult CNS
  • Largely neuron-specific
  • Axonal predominant
  • Alternatively spliced
  • Microtubule-associated protein
  • Phosphoprotein (S,T,Y)
  • Highly phosphorylated during development and in AD
19
Q

How can processing of tau affect binding to microtubules

A
  1. )Tau splicing affects binding to microtubules
    - 4R tau binds MTs 3 times more strongly than 3Rtau
    - 4R tau assembles MTs more efficiently than 3R tau
    - Normally 4R:3R tau is~1
    - Disease 4R:3R tau is~2-3
  2. )Tau phosphorylation affects binding to microtubules
    - Tau phosphorylation is possible on 79 different residues
    - 30 of these are actively phosphorylated
    - Tau is phosphorylated by specific kinases
    - Hyperphosphorylation of tau leads to aggregation pathology
    - GSK-3 is a key kinase under pathological conditions
20
Q

State the taupathies (familial and sporadic)

A
  • AD
  • Fronto-temporal dementia with parkinsonism linked chromosome 17(FTDP)
  • progressive supranuclear palsy(PSP)
  • Corticobasal degeneration (CBD)
  • Pick’s disease (PiD)
  • Down’s syndrome
  • Postencephalitic Parkinsonism
  • Niemann Pick’s disease

Tau aggregates= a feature of normal ageing

  • aggregation of tau
  • hyperphosphorylation of tau
  • altered expression of tau
21
Q

What causes tangles in AD

A

Tau mutations which lead to tau dysfunction

22
Q

Outline bio markers in AD

A
  • capture emerging pathology
  • for developing treatments
  • for early diagnosis
  • Not always a strong correlation between bio marker and disease symptoms
  • Can be a feature of healthy ageing (eg ~25% brains with high amyloid- diagnostic for AD) can be cognitively normal just prior to death
  • May not be specific for disease
  • Pathology may be treatable eg remove amyloid plaques and correlated with biomarker but no improvement with symptoms eg amyloid immunisation-solanezumab
23
Q

Outline drug targets in AD

A
  • Based around pathology and symptoms
  • Symptomatic benefit: cognitive symptoms; non-cognitive behavioral change
  • Disease showing/modification strategies
  • Disease prevention
24
Q

Outline the cholinergic hypothesis

A
  • Cholinergic neurons are lost first and most in AD
  • Choline acetyl transferase (CHaT) markers lost in AD
  • Reduced choline uptake and ACh release in AD
  • Neuronal loss in cholinergic nuclei in AD
  • Cholinergic neurons are essential for memory
  • Inhibition of cholinergic function results in cognitive loss
  • Lesioning of cholinergic tracts also results in cognitive loss
  • Nicotine stimulates rapid info processing
  • Cholinergic rich grafts restore memory functioning
25
Q

Outline the options to enhance cholinergic function

A
  1. )Drive synthesis
  2. )Enhance release
  3. )Prevent breakdown:
    - donepezil
    - rivastigmine
    - galantamine
  4. )Post-synaptic stimulation
    - galantamine
26
Q

Outline the molecular approaches to disease modification

A
  • BACE inhibitors
  • Anti-fibrillation
  • Abeta degradation: immunisation,neprilysin insulin-like degrading enzyme
  • GSK-3 inhibition
  • Anti-tau aggregation(methylene blue)
  • Anti-inflammatories (NSAIDs)
  • Anti oxidants

Ageing block (16 decks)

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