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Table 2 Aβ-lowering cognitive benefit in TgAPP mice

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

Aβ-lowering method Brain Aβ lowering (%) Observed functional benefits Mouse strain Reference
BACE1-/- KO >90% Contextual fear conditioning, Morris water maze, social recognition Tg2576; 5xFAD [1416]
BACE+/- KO 12% in young mice Contextual fear conditioning, conditioned taste aversion PDAPP; 5xFAD [1720]
Presenilin conditional forebrain KO 75% No benefit (novel object recognition in 3- to 6-month-old mice) APP [V717I] [25]
Presenilin conditional forebrain KO 55% in young mice Contextual fear conditioning and Morris water maze in young but not old mice APP J20 [26]
TgAPP conditional allele ≥70% new Aβ; no effect on steady-state Aβ42 levels Two trial Y maze; plus water maze; radial arm water maze Repressible TgAPP [27]
Cystatin C KO 40% (Aβ); 60% (Aβ42) in young mice Morris water maze APP J20 [28]
GRL-8234 (BACEi) 35-50% plaque after 7 months Morris water maze Tg2576 [31]
TAK-070 (BACEi) 20% plaque after 7 weeks Y-maze, Morris water maze, novel object recognition Tg2576 [29]
Trihydroxychalcone (BACEi) 50-60% plaque after 106 days Morris water maze APP-PS1 [28]
DAPT (GSI) single dose 25% at 8 hours Contextual fear conditioning Tg2576 [32]
DAPT (GSI) repeat dose 35% after 4 days Morris water maze Ts65Dn [34]
Begacestat (GSI) single dose 25-35% at 4 hours Contextual fear conditioning Tg2576 [33]
Semagacestat/ LY450139 (GSI) No change 1 mg/kg; 25-30% 10 mg/kg Y maze benefit at 1 mg/kg after single dose; no benefit at 10 mg/kg or 8-day repeat dosing Tg2576 [35]
Avagacestat/ BMS-708163 (GSI) No change 1 mg/kg; 25-30% 10 mg/kg Y maze benefit at 1 mg/kg after single dose; no benefit at 10 mg/kg or 8-day repeat dosing Tg2576 [35]
  1. Aβ, amyloid-β; BACE, β-site APP-cleaving enzyme; BACEi, β-site APP-cleaving enzyme inhibitor; GSI, γ-secretase inhibitor; KO, knock out; TgAPP, APP transgenic.