CSB332H1 Lecture Notes - Lecture 19: Psen1, Presenilin, Passive Immunity
14 May 2018
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Professor
Lecture 19: Alzheimer’s Disease & Possible Treatments
Why do we have APP?
• Amyloid-b fragments activate the immune/compliment system and this is associated with
Alzheimer’s Disease – over activation of the immune system
o Amyloid-b can be immunogenic: structure resembles LL-37 antimicrobial protein
Alzheimer’s Disease Mouse Models:
• APP and TAU mice models have similar pathologies as seen in human AD
o APP - Ab accumulation: display pathology in the cortex and hippocampus
o TAU – NFT formation: display pathology in the amygdala and hippocampus
ð APP and pR5 models have an mThy1.2 promotor – drives expression in all neuronal cells
Possible Treatment Strategies:
• Pathology of AD involves:
(1) intracellular aggregation of hyper-phosphorylated Tau; NFT
(2) extracellular aggregates of amyloid-
b
Target/Prevent Amyloid-
b
:
a) Stimulate a-secretase; will favor the physiological pathway
b) Inhibit g-secretase to prevent formation of ab-40/42
c) Passive immunization – generate antibodies specific to ab plaques (anti-ab antibodies)
d) Active immunization – develop antibodies to eliminate ab plaques
Target/Prevent NFTs:
a) Inhibit tau aggregation – by inhibiting kinases, or inducing phosphatases
b) Increase microtubule stabilization (i.e. transgenic mechanism) to prevent from degenerating
c) Increase of tau clearance (protein is intracellular) – may lead to potential problems?
Genetics of AD:
• Majority of AD is sporadic – majority is non genetic, therefore possible environmental causes?
• Familial cases only account for 5% – individuals have the clinical symptoms
o 50% of familial cases can be explain by mutations in APP or Presenilins 1&2
APP Mutations:
• Down Syndrome patients have an extra copy of chromosome 21 – which encodes for APP
o Patients have an ‘extra load’ of APP – and mutations alter APP processing:
§ Increase cleavage via b-secretase pathway
§ Increase ab42:ab40 ratio – 42 is more toxic; has fibrillogenic potential
Presenilin Mutations:
• g-secretase is membrane bound & has 4 subunits: Presenilin 1 or 2, Nicastrin, APH-1, PEN-2
o Presenilin subunit only has protease activity
§ Mutations in Presenilin lead to an increase ab42:ab40 ratio
