Treatments for AD Flashcards
why are current drugs not disease modigying
because they target neuronal populations, and these diminish over time
what are the 5 key arguments for targeting Ab
- amyloid deposits = early path evidence, neuriticc plaques = key diagnostic criterion
- peripheral amyloidoses, amyloid burden drives tissue dysfunction
- Ab oligomers = acute synatpic toxic effects, plaque derived Ab fibrils = pro-inflam effects => neuronal toxicity
- APOE4 = incr amyloid burden
- all mutations that cause familial early onset AD inc Ab42 production/ratio of Ab42 commpared to less aggregation prone aB40 isform
describe y-secretase inhibitors
1st target in amyloid pathway
reduce plasma and soluble brain Ab in mice after few hours in one admin
can effect other bio essential substrates
notch signalling protein (needed ofr diff + prolif of embryonic T/B cells)
some clin trials show poor side effects + no cog improvement or worse cog, or liver toxicity
describe b secretase inhibitors
KO mice appear health but abnorm with spatial/reference memory/temporal associate mem
difficulty of BBB penetration
phase 1 dose-dependent red plasma Ab lvls for extended period time some drugs in phase 2/3, some halted for liver effects
stim a-secretase pathway
cleaves APP within Ab domain + dec lvls neurotoxic + pathogenic Ab peptide
inc lvls neuroprotective APPsa
act M1 msucarinic ACh rec stim a-secretase cleavage
selectivity is a problem within most of these cases
inibiting Ab aggregation
small mol drugs interfere with Ab=Ab peptide interactions
trials = no efficacy, or no sig cog diff b/groups… but CSF Ab42 lvls sig dec, or metal protein attenuating compound, improved exec function + dc CSF Ab42
enhancing Ab clearnace
-several jeyt enzymes in Ab degardation have been identified eg proteases neprilysin, plasmin, insulin-degradaing enzyme
difficult to act enzymes, may block inhib of protease
-move Ab from CNS to periphery for degradation
RAGE rec mediate Ab influx -> brain
RAFE inhibitor worsened cog impairment at high dose _ ineffective at low dose
lrp-1 mediates efflux of Ab out of brain
active immunotherapy for AD
active (vax) and passive (monoclonal antibodies)
active imm against Ab42 in transgenic mice => dec plaques + improve cog function
BUT other trials discontinued bc patients develope meningoencephalitis
describe passive immunotherapy for AD
anti-ab42 antibodies are injected
bapineuzemab = discontinued when results weren’t as good as predicted
others have failed to show slowing of cog functonal decline
others are still in trial
describe solanezumab
passive immunotherapy
humanised monoclonal IgG1 antibody directed against mid-domain Ab peptide
injection into mouse = reversed mem deficits in APP transgenic mouse models wo/clearing amyloid plaques => targets soluble amyloid
updates to solanezumab
july 2015 = appeared to slow progression of mild AD after failing twice in severe AD in 2012
2016 = focus changes to look at whether drug can stall changes early on in AD
only look at effect on cog deline - nothing on activities of daily living
1st drug for mild AD
400mg dose every 4 weeks did not affect cog dec
claims there is AD flu shot BUT experiements were elegnatly designed
describe the success rate of AD treatments
0.4%, out of 413 clin trials
14 vax programs targeting tau atm
18 tagrgeting amyloid have failed
tau treatment approaches - kinase inhib
17 sites of Sp/TP protein kinases + sites additional sites target of diff kinases
difficult to identify key pathogenic kinase
gen specific brain penetrant kinase inhib = suoitable chronic dosing = challenging bc side effects = preclinical
tau clearance activator
enhance clearance prevents toxicity
methylene blue = dissolve tau filaments in vitro = prevent tau agg (cell-based models)
trial = sigdiff on AD assessment scale in middle dosed group
inflammation targeting strategies
microglia, astrocytes, markers of inflam = inc in AD
50% dec AD risk in long term NSAIDa
trials are disappointing, but maybe need diff target
neuroinflammation may be beneficial
