| First Author | Sesele K | Year | 2013 |
| Journal | Aging Cell | Volume | 12 |
| Issue | 6 | Pages | 1032-40 |
| PubMed ID | 23826707 | Mgi Jnum | J:210209 |
| Mgi Id | MGI:5569714 | Doi | 10.1111/acel.12131 |
| Citation | Sesele K, et al. (2013) Conditional inactivation of nicastrin restricts amyloid deposition in an Alzheimer's disease mouse model. Aging Cell 12(6):1032-40 |
| abstractText | Production of Abeta by gamma-secretase is a key event in Alzheimer's disease (AD). The gamma-secretase complex consists of presenilin (PS) 1 or 2, nicastrin (ncstn), Pen-2, and Aph-1 and cleaves type I transmembrane proteins, including the amyloid precursor protein (APP). Although ncstn is widely accepted as an essential component of the complex required for gamma-secretase activity, recent in vitro studies have suggested that ncstn is dispensable for APP processing and Abeta production. The focus of this study was to answer this controversy and evaluate the role of ncstn in Abeta generation and the development of the amyloid-related phenotype in the mouse brain. To eliminate ncstn expression in the mouse brain, we used a ncstn conditional knockout mouse that we mated with an established AD transgenic mouse model (5XFAD) and a neuronal Cre-expressing transgenic mouse (CamKIIalpha-iCre), to generate AD mice (5XFAD/CamKIIalpha-iCre/ncstn(f/f) mice) where ncstn was conditionally inactivated in the brain. 5XFAD/CamKIIalpha-iCre/ncstn(f/f) mice at 10 week of age developed a neurodegenerative phenotype with a significant reduction in Abeta production and formation of Abeta aggregates and the absence of amyloid plaques. Inactivation of nctsn resulted in substantial accumulation of APP-CTFs and altered PS1 expression. These results reveal a key role for ncstn in modulating Abeta production and amyloid plaque formation in vivo and suggest ncstn as a target in AD therapeutics. |
