Amelioration of cognitive deficits in plaque-bearing Alzheimer's disease model mice through selective reduction of nascent soluble A beta 42 without affecting other A beta pools

Given that amyloid- beta 42 (A beta 42) is believed to be a culprit in Alzheimer's disease (AD), reducing A beta 42 production should be a potential therapeutic approach. gamma -Secretase modulators (GSMs) cause selective reduction of A beta 42 or both reduction of A beta 42 and A beta 40 without affecting total A beta through shifting the gamma -cleavage position in amyloid precursor protein. We recently reported on GSM-2, one of the second-generation GSMs, that selectively reduced brain A beta 42 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 A beta 42 only in 10-month-old mice. In contrast, GSM-2 markedly reduced newly synthesized soluble A beta 42 in both 10- and 18-month-old mice with similar efficacy when measured using the stable isotope-labeling technique, suggesting that nascent A beta 42 plays a more significant role than plaque-associated soluble A beta 42 in the cognitive deterioration of Tg2576 mice. These findings further indicate the potential utility of approach to reducing A beta 42 synthesis in AD therapeutic regimens. In Alzheimer's disease, gamma -secretase modulators (GSMs) cause selective reduction of A beta 42 and/or A beta 40 without affecting total A beta through shifting the gamma -cleavage position in amyloid precursor protein. Here, we demonstrate that eight-day treatment with GSM-2 significantly ameliorated cognitive deficits as measured by a Y-maze task in plaque-bearing Tg2576 mice. Stable isotope-labeling revealed that GSM-2 markedly reduced de novo A beta 42 in the brain of these mice and additionally reduced brain soluble A beta 42 in 10-month-old (but not 18-month-old) mice, suggesting a significant role of nascent A beta 42 in cognitive deterioration. Veh = vehicle (control with deficits in spatial working memory). Read the Editorial Highlight for this article on doi: 10.1111/jnc.12156.