Alzheimer's Flashcards
Pre-clinical models in Alzheimer’s? (Acute)
Acute Pharmacological Model
Amyloid-beta injections into brain and then NOR to test cognition
Issue with amyloid being cleared and configurations
Brains can be tested post-mortem to find pharmacological targets
Pre-clinical models in Alzheimer’s? (Chronic)
Transgenic Mouse Model
APP gene, Presenilin gene, Tau gene - overproduction of amyloid, then cognitive tests
Relevance to sporadic AD is questionable (overproduction isn’t the problem)
See when amyloid becomes an issue
Novel targets in Alzheimer’s? (Amyloid)
Secretase modulators - BACE inhibitor, reduce production of amyloid beta
Anti-Aggregants - Prevent formation of plaques
Immunotherapies - Target plaques and break them down
Problems with novel targets? (Amyloid)
Secretase - Once symptomatic production has slowed, crossing BBB, inhibits other BACE functions
Anti-Aggregants - Crossing BBB, configurations make targets difficult, what stages will it work, affect clearance
Immunotherapies - Configuration issues, uncertain behaviours in brain, breakdown products
Sterile inflammation initiation?
Contact with amyloid, inflammasome NLRP3 formed and caspase-1 is activated
Caspase-1 cleaves pro-IL-1 beta to form interleukin 1 beta, released from microglial cell
Evidence of inflammation as cause of cognitive deficits?
Water test - Deficit restored when amyloid is still present but not inflammasome
Fenamates mechanism of action?
Prevents microglial activation, stops inflammation cascade
Mefenamic acid in acute model?
Deficit restored after 13 days treatment following amyloid beta injection (tested 24 hours after treatment stopped), still stopped for 21 days and deficit still restored
Mefenamic acid in transgenic model?
Chronic treatment for 2-3 weeks by implanted osmotic mini pumps
Cognitive deficit reversed
When brains tested after, less microglial activation and IL-1 beta
