Alzheimers Flashcards
What is the difference between a normal brain and an Alzheimer’s brain
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
How is B-amyloid produced
Peptide produced from amyloid precursor protein (APP) by action of proteases (secretases)
APP is a transmembrane glycoprotein
What secretases cleave APP
A B and Y
if cleaved by B and Y then B-amyloid is produced causing toxicity-plaques.
What increases the proportion of the toxic Amyloid B 42
Mutations In APP
increasing Y secretase activity by mutations of presenilin
What is APP usually cleaved by to form a soluble APP and C-terminal fragment
A-secretase - no plaque
How is B-amyloid deposited
Monomer- oligomer- fibril- amyloid-B plaques with microglia and astrocytes
What is the underlying theory of disease progression of alzheimers
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
What are neurofibrillary tangles
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
In summary explain the reason for neuronal cell death in AD
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
What pathways are ACh in
Nucleus basalis to cortex
Septal nuclei to hippocampus (memory)
What neurochemical changes are observed in AD
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
Hy does downs syndrome predispose to AD
APP is on chromosome 21 - 3 copies in down’s -therefore more expression of APP more cleavage and more plaques
What may cause early onset AD
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.
What causes late onset AD
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
What drugs are used in AD
anticholinesterases- donepezil, rivastigmine, galantamine
NMDA antagonists- memantine
