CJH332H1 Lecture Notes - Lecture 20: Amyloid Precursor Protein Secretase, Presenilin, Psen1
Lecture 20: Alzheimer’s Disease
Creating AD mouse models
• PSEN1 mutations are inheritable form of AD
• We do’t ko hich odels doiates ad iitiates AD
- APP or Tau modified mice
• Different proteins (tau and APP) have characteristic patterns in where they start accumulate
- APP in cortex, hippocampus → spreads over cortex and hippocampus
- Tau in amygdala, hippocampus → slower spreading
• APP23 mouse AB plaque stained with congo red (staining monoamines) also shown in human (AD)
• pR5 mouse (hyperphosphorylated tau) show similar intracellular inclusions that eventually degenerate. This is
also shown in human (AD)
- Extracellular b-amyloid formation AND intracellular NFTs involving hyperphosphorylated tau
• Both APP23 and pR5 use Thy1.2 promoter which allows expression in all over the brain (all types of neurons)
Possible treatment strategies
• AB fibrils/plaques (none of them useful for clinical trials)
- Stimulating a-secretase will decrease b-amyloid plaques
- Inhibiting y-secretase will stop ultimate formation of B-amyloid
- Passive immunization with anti-AB plaque antibodies (immune system to clear them up)
- Active immunization with AB peptides
• Tau fibrils/NFTs
- Inhibition of tau aggregation
- Inhibiting kinases
- Stimulators of phosphatases to remove phosphates
- Increasing MT stabilization (transgenic methods)
- Increase of tau clearance (potential problem with this – tau is intracellular protein and is released to ECM)
Genetics of AD
• While sporadic AD is majority AD patients (non genetic in origin), familial AD (FAD) accounts for only 5%
• FAD manifests earlier (around 40-50 years of age) compared to >65 years of age in sporadic instances
• Despite this drastic difference in disease onset, symptoms are identical
• Only 50% of FAD (5%) can be explained by known mutations in genes encoding APP and presenilins 1 and 2
APP mutations
• Relatively rare (~12%)
• Aerage age of oset is i the early 50’s
• Most Down Syndrome patients develop AD after age 40 since they have an extra copy of chromosome 21
- On it has a location that encodes for APP (extra load of APP → those who have DS develop AP symptoms)
• Most mutations alter APP processing by:
- Increasing cleavage via the B-secretase pathway (more substrate/APP, more secretase)
- Increasing the AB42/40 ratio (AB1-42 fragment more toxic/fibrilionic potential than AB40)
Presenilins (PS)
• Y-secretase complex is composed of 4 constituents:
- Presenilin (1 or 2), Nicastrin, APH-1 and PEN-2
• PS component is the only one with proteolytic activity (that can cut peptides)
find more resources at oneclass.com
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Document Summary
Creating ad mouse models: psen1 mutations are inheritable form of ad, we do(cid:374)"t k(cid:374)o(cid:449) (cid:449)hich (cid:373)odels do(cid:373)i(cid:374)ates a(cid:374)d i(cid:374)itiates ad. App or tau modified mice: different proteins (tau and app) have characteristic patterns in where they start accumulate. App in cortex, hippocampus spreads over cortex and hippocampus. Tau in amygdala, hippocampus slower spreading: app23 mouse ab plaque stained with congo red (staining monoamines) also shown in human (ad, pr5 mouse (hyperphosphorylated tau) show similar intracellular inclusions that eventually degenerate. Extracellular b-amyloid formation and intracellular nfts involving hyperphosphorylated tau: both app23 and pr5 use thy1. 2 promoter which allows expression in all over the brain (all types of neurons) Possible treatment strategies: ab fibrils/plaques (none of them useful for clinical trials) Inhibiting y-secretase will stop ultimate formation of b-amyloid. Passive immunization with anti-ab plaque antibodies (immune system to clear them up) Active immunization with ab peptides: tau fibrils/nfts.
