| First Author | Mitani Y | Year | 2013 |
| Journal | J Neurochem | Volume | 125 |
| Issue | 3 | Pages | 465-72 |
| PubMed ID | 23240999 | Mgi Jnum | J:196331 |
| Mgi Id | MGI:5487736 | Doi | 10.1111/jnc.12125 |
| Citation | Mitani Y, et al. (2013) Amelioration of cognitive deficits in plaque-bearing Alzheimer's disease model mice through selective reduction of nascent soluble Abeta42 without affecting other Abeta pools. J Neurochem 125(3):465-72 |
| abstractText | Given that amyloid-beta 42 (Abeta42) is believed to be a culprit in Alzheimer's disease (AD), reducing Abeta42 production should be a potential therapeutic approach. gamma-Secretase modulators (GSMs) cause selective reduction of Abeta42 or both reduction of Abeta42 and Abeta40 without affecting total Abeta 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 Abeta42 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 Abeta42 only in 10-month-old mice. In contrast, GSM-2 markedly reduced newly synthesized soluble Abeta42 in both 10- and 18-month-old mice with similar efficacy when measured using the stable isotope-labeling technique, suggesting that nascent Abeta42 plays a more significant role than plaque-associated soluble Abeta42 in the cognitive deterioration of Tg2576 mice. These findings further indicate the potential utility of approach to reducing Abeta42 synthesis in AD therapeutic regimens. |
