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Table 3 γ-Secretase modulators and selective Aβ42-lowering benefit

From: Interpreting Alzheimer’s disease clinical trials in light of the effects on amyloid-β

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 [5053]
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]
  1. Aβ, amyloid-β; ICV, intracerebroventricular; mpk, mg/kg; Tg, transgenic.