Alzheimers Flashcards
What plaques develop
Amyloid Beta
What do solute AB do
Increase glutamate release and change synaptic transmission
What enzymes act on amyloid precursor protein
alpha secretase
b secretase
y secretase
What does a secretase produce
sAPP. Non amyloidgenic
what does b/y-sec make
AB 40 or AB42
Pathology of AB
Aggregation esp. AB42 Lack of clearance Oligomer Amyloid Plaques Inflammation, oxidative stress LTP impairment from AB
Tangles pathology
Oligomers activate kinases
Kinases convert tau to tau PPP
Tau PPP causes neurofibrillary tangles
Other hypotheses for AD
Failure of autophagy
Loss of Ca homeostasis due to excitotoxicity
Inflammation - injury causes disease, chronic inflam state
Oxidative damage
Reasons to doubt AB hypothesis
Accumulation of AB high plaque load in rats and humans doesnt = Alzheimers
When plaque load reduced by immunotherapy, no improvement
Percentage of patients with high plaque load but no AD
25%
Limitations of mouse model for AD (2)
Mice do not get tau tangels despite plaque load
Mice overexpress TREM2, which increases phagocytosis
Microglia actions around AB
They cluster around synapses with a high plaque load, and remove them to save the axon
What is tau normal function
Part of microtubules that transport materials down axons
What is tau phosphorlayed by
GSK-35
What does phosphorylated tau do
Dissociates from microtubules and becomes part of paired helical filament
Helical filaments then can aggregate, causing neurofibrillay tangles
Can impair axonal transport
