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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.