Table 3.

γ-Secretase modulators and selective Aβ42-lowering benefit

Selective Aβ42-lowering method	Brain Aβ42 lowering (%)	Observed cognitive or pathological benefits in deficient Tg mouse	Mouse strain	Reference
ICV injection of preaggregated Aβ42/Aβ40	Aβ42/40 3:7 ratio; 1:9 ratio inactive	Passive avoidance and contextual fear conditioning	Wild type; intraventricular Aβ administration	[44]
BRI-Aβ40 and BRI-Aβ42 transgenes	50-400% increased Aβ40 (decreased 42/total ratio)	60-90% decreased plaque; improved survival; however, these mice exhibited no Aβ-dependent cognitive phenotypes	Tg2576 and Tg-Aβ40	[46,47]
EVP-0015962	50% after single 30 mpk dose	Contextual fear conditioning, gliosis 75% plaque load, after 50 weeks at 60 mpk/day	Tg2576	[49]
CHF5074	No significant change (4–9 month treatment)	Contextual memory, 50-75% decreased plaque burden, astrogliosis, synaptophysin levels, neurogenesis	Tg2576	[50-53]
GSM-2	0-30% at 0.1-3 mpk, respectively	Y maze improvements at 0.1-3 mpk in mice aged 5.5 months	Tg2576	[35]
GSM-2	50-60% nascent Aβ 2 hours after 10 mpk	Y maze and plaque pathology in mice aged 10–18 months	Tg2576	[36]
JNJ40418677	50% max lowering 30 mpk single dose	Up to 96% decreased plaque area and number after 7 months at 120 mpk/day	Tg2576	[55]
Compound 4	40% decrease 100 mpk single dose	48-76% decrease of plaque Aβ after 7 months at 50 mpk/day	Tg2576	[54]

Aβ, amyloid-β; ICV, intracerebroventricular; mpk, mg/kg; Tg, transgenic.