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 | |
BACE+/- KO | 12% in young mice | Contextual fear conditioning, conditioned taste aversion | PDAPP; 5xFAD | |
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] |