0917 - Alzheimer's Disease Flashcards
Outline why AD is a neurodegenerative disease
Rapid progression following a ‘very long incubation’ (50yrs). There is physical damage and destruction of neurons.
Hits variable areas neocortex depending on patients, but spares the visual, motor, and somatosensory cortices.
ACh first neuromodulator affected.
Explain the make-up of plaques and tangles
Plaque - Appears in nerve tissue and around blood vessels. Extracellular deposit of b-Amyloid oligomeres in centre, and a corona of dystrophic nerve terminals filled with hyperphosphorylated tau around it. Corona is where disease is most active.
Tangles - Intracellular deposits of hyperphosphorylated and incorrectly phosphorylated microtubule-associated tau assembled into paired helical filaments. Due to phosphorylation problems, they clump together and no longer support the microtubule, meaning no axonal transport of mitochondria to/from the synapse.
Recognise why beta-amyloid and presenilins have multiple actions both physio- and pathologically
Monomeres are neurotrophic. Head Important during neuronal development and for apoptosis. Beta maintains synapses, Tail important for calcium homeostasis.
Cytotoxic when it becomes bigger than 40-42 AAs, as an oligomere. Causes oxidation, excitotoxicity, inflammation, and tau phosphorylation.
Presenilin very important in gamma secretase in determining where the APP is cleaved, so critical in forming 40-42AA ABs. Also form a calcium leak channel on ER, which can over-activate beta-secretase, leading to more AB.
Describe some cell-biological mechanisms causing AD
Oligomeres of AB can form insoluble sheets, precipitating plaques.
Presinilin forming Ca leak channel, link with AB
Type of secretase.
Outline why AD is largely a synaptic disease
Synaptic efficacy is smaller due to AMPA-type EPSPs being reduced. You also get reduced numbers of synapses, due to a drop in the density of spines (sites of excitatory synapses) when exposed to beta-amyloid oligomers.
