Amelioration of cognitive deficits in plaque-bearing Alzheimer's disease model mice through selective reduction of nascent soluble Aβ42 without affecting other Aβ pools.

Given that amyloid-β 42 (Aβ42) is believed to be a culprit in Alzheimer's disease (AD), reducing Aβ42 production should be a potential therapeutic approach. γ-Secretase modulators (GSMs) cause selective reduction of Aβ42 or both reduction of Aβ42 and Aβ40 without affecting total Aβ through shifting the γ-cleavage position in amyloid precursor protein. We recently reported on GSM-2, one of the second-generation GSMs, that selectively reduced brain Aβ42 level and significantly ameliorated cognitive deficits in plaque-free 5.5-month-old Tg2576 AD model mice. Here, we investigated the effects of GSM-2 on 10-, 14-, and 18-month-old mice which had age-dependent increase in amyloid plaques. Eight-day treatment with GSM-2 significantly ameliorated cognitive deficits measured by Y-maze task in the mice of any age. However, GSM-2 reduced brain soluble Aβ42 only in 10-month-old mice. In contrast, GSM-2 markedly reduced newly synthesized soluble Aβ42 in both 10- and 18-month-old mice with similar efficacy when measured using the stable isotope-labeling technique, suggesting that nascent Aβ42 plays a more significant role than plaque-associated soluble Aβ42 in the cognitive deterioration of Tg2576 mice. These findings further indicate the potential utility of approach to reducing Aβ42 synthesis in AD therapeutic regimens.