Alzheimers Flashcards

1
Q

What is the difference between a normal brain and an Alzheimer’s brain

A

Smaller- atrophy
Neuronal and synaptic loss
Ventricles enlarged
Decrease of hippocampus size
Plaques containing B-amyloid peptides
neurofibrillary tangles
losses in cholinergic, GABAergic and monoaminergic transmitter systems

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2
Q

How is B-amyloid produced

A

Peptide produced from amyloid precursor protein (APP) by action of proteases (secretases)
APP is a transmembrane glycoprotein

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3
Q

What secretases cleave APP

A

A B and Y
if cleaved by B and Y then B-amyloid is produced causing toxicity-plaques.

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4
Q

What increases the proportion of the toxic Amyloid B 42

A

Mutations In APP
increasing Y secretase activity by mutations of presenilin

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5
Q

What is APP usually cleaved by to form a soluble APP and C-terminal fragment

A

A-secretase - no plaque

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6
Q

How is B-amyloid deposited

A

Monomer- oligomer- fibril- amyloid-B plaques with microglia and astrocytes

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7
Q

What is the underlying theory of disease progression of alzheimers

A

Soluble Amyloid-B oligomers = affects long term potentiation, can cause cell death, can cause NMDA Ca+ influx, synaptic dysfunction

Plaque associated protein added into fibril forming extracellular plaque = Inflammatory response- cytokine release- mitochondrial damage - oxidative stress -> neuronal cell death
Direct cytotoxic effects

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8
Q

What are neurofibrillary tangles

A

Tau becomes hyper phosphorylated
Tau usually stabilises microtubules (imp. for axonal transport)
Tau usually binds to microtubules to stabilise, however when hyper phosphorylated they detach from microtubule and aggregate to form paired helical filaments that tangle
Tau cant associate w microtubules and therefore loss of axonal transport

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9
Q

In summary explain the reason for neuronal cell death in AD

A

APP cleaved by B and Y secretase causing aggregation forming oligomers forming plaques= oxidation/ stress
Hyperphosphorylation of Tau protein, AB can influence this by inflammation.
Forms neurofibrillary tangles
Neuron death

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10
Q

What pathways are ACh in

A

Nucleus basalis to cortex
Septal nuclei to hippocampus (memory)

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11
Q

What neurochemical changes are observed in AD

A

Loss cholinergic neurons in nucleus basalis to cortex (basal forebrain) and hippocampus
Less choline acetyltransferase and other markers (AChE eg) in hippocampus and cortex
ACh content lowered

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12
Q

Hy does downs syndrome predispose to AD

A

APP is on chromosome 21 - 3 copies in down’s -therefore more expression of APP more cleavage and more plaques

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13
Q

What may cause early onset AD

A

Mutations of
*APP - cleavage of APP favouring Amyloid B 42 which forms plaques
*Presenilin (PSEN1 PSEN2) - part of Y secretase - mutation increases more Amyloid B42 production. PEN1 more common
*Tau mutations - increased phosphorylation, neurofibrillary tangles.

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14
Q

What causes late onset AD

A

4 types of ApoE gene
Lipid binding lipoprotein
Transports lipids
APOE4 linked with risk of AD
get them from parents- if carry 2 ApoE4 alleles gives highest risk
ApoE2 decr. risk
Found in plaques- role in clearing plaques

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15
Q

What drugs are used in AD

A

anticholinesterases- donepezil, rivastigmine, galantamine
NMDA antagonists- memantine

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16
Q

How do acetylcholinesterase inhibitors help AD

A

Selective loss of cholinergic neurones.
Boosts ACh therefore allows activity at synapses to make up for neuronal loss.
Release of ACh and works. AChE breaks down to choline and acetate. Choline taken back up into presynaptic terminal. Blocking AChE allows more ACh in synapse for effect.
Galantamine also blocks Butyl choline esterase which also breaks down Acetyl choline. ALso a nicotinic receptor modulator. Positive allosteric modulator- increases downstream actions of nicotinic receptors. If binds to presynaptic terminal, can increase release of ACh

17
Q

How does memantine work for AD

A

Non competitive NMDA antagonist
Therefore limits excitotoxicity
Glutamate in excess will cause excitotoxicity and plays a role in neuronal cell death in AD - as neuronal cells die, release of cell death and causes more cytotoxicity.
Therefore this drug can inhibit neuronal cell death in AD allowing cognitive improvement in AD