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

• Published in: Journal of neurochemistry Vol. 125; no. 3; p. 465
• Main Authors: Mitani, Yasuyuki, Yarimizu, Junko, Akashiba, Hiroki, Shitaka, Yoshitsugu, Ni, Keni, Matsuoka, Nobuya
• Format: Journal Article
• Language: English
• Published: New York Blackwell Publishing Ltd 01-05-2013
• Subjects: Alzheimer's disease; Cognition & reasoning; Drug therapy
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12125

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. Read the Editorial Highlight for this article on doi: 10.1111/jnc.12156. [PUBLICATION ABSTRACT]