To: tuck who wrote (429 ) 3/9/2015 12:42:49 PM From: tuck Respond to [Is gamma secretase even a good target in Alzheimer's?]Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s DiseaseDan Xia Hirotaka Watanabe Bei Wu Sang Hun Lee Yan Li Evgeny Tsvetkov Vadim Y. Bolshakov Jie Shen 5 Raymond J. Kelleher III5 dx.doi.org Presenilin-1 mutations cause complete loss of PS1 function in vivo•FAD-linked Presenilin-1 mutations abolish ?-secretase activity•FAD-linked Presenilin-1 mutations impair hippocampal memory and synaptic function•FAD-linked Presenilin-1 mutations cause age-dependent neurodegenerationPresenilin-1 (PSEN1 ) gene are the major cause of familial Alzheimer’s disease (FAD). How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI) mice carrying the FAD mutation L435F or C410Y. Remarkably, KI mice homozygous for either mutation recapitulate the phenotypes of Psen1 -/- mice. Neither mutation altered Psen1 mRNA expression, but both abolished ?-secretase activity. Heterozygosity for the KI mutation decreased production of Aß40 and Aß42, increased the Aß42/Aß40 ratio, and exacerbated Aß deposition. Furthermore, the L435F mutation impairs hippocampal synaptic plasticity and memory and causes age-dependent neurodegeneration in the aging cerebral cortex. Collectively, our findings reveal that FAD mutations can cause complete loss of Presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism.<<
