Yasuyuki Mitani, Junko Yarimizu, Hiroki Akashiba, Yoshitsugu Shitaka, Keni Ni and Nobuya Matsuoka Amelioration of cognitive deficits in plaque-bearing Alzheimer's disease model mice through selective reduction of nascent soluble Aβ42 without affecting other Aβ pools Journal of Neurochemistry 125
In Alzheimer's disease, γ-secretase modulators (GSMs) cause selective reduction of Aβ42 and/or Aβ40 without affecting total Aβ through shifting the γ-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 Aβ42 in the brain of these mice and additionally reduced brain soluble Aβ42 in 10-month-old (but not 18-month-old) mice, suggesting a significant role of nascent Aβ42 in cognitive deterioration. Veh = vehicle (control with deficits in spatial working memory).
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