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- W1978363460 abstract "Familial Alzheimer's disease (FAD) is linked to mutations in the presenilin (PS) homologs. FAD mutations have several cellular consequences, including exaggerated intracellular Ca2+ ([Ca2+]i) signaling - enhanced sensitivity to agonists of ER Ca2+ release and increased magnitudes of [Ca2+]i signals. Single channel recordings suggest exaggerated [Ca2+]i signaling is due to a gain-of-function interaction between FAD mutant PS and the inositol 1,4,5-trisphosphate receptor (InsP3R). However, the in vivo significance of the PS-InsP3R interaction to exaggerated [Ca2+]i signaling and the contribution of exaggerated [Ca2+]i signaling to the development of AD are unknown. If exaggerated [Ca2+]i signaling is InsP3R-dependent, we hypothesize that decreasing InsP3R protein expression will normalize [Ca2+]i signaling. Therefore, we crossed the Opisthotonus (Opt) mouse, deficient in InsP3R1 protein, to the PS1M146V knock-in (PS1KIN) AD mouse model to investigate the contribution of InsP3R-1-mediated [Ca2+]i release to exaggerated [Ca2+]i signaling, and the role of exaggerated [Ca2+]i signaling to the AD-like phenotypes of this mouse model. We observed that the Opt allele normalizes exaggerated [Ca2+]i release in vitro and ex vivo. Interestingly, in young (5wk) and mature (3 mth) PS1KIN mice we observed that the Opt allele normalized aberrantly activated hippocampal biochemical pathways and the enhancement of CA3-CA1 early long-term potentiation present in these mice - phenotypes that mirror the early hippocampal hyperactivity in patients that later develop AD. These findings indicate that FAD mutant PS-associated exaggerated [Ca2+]i signaling is InsP3R1-dependent and a early event in Alzheimer's disease." @default.
- W1978363460 created "2016-06-24" @default.
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- W1978363460 date "2013-01-01" @default.
- W1978363460 modified "2023-09-28" @default.
- W1978363460 title "Exaggerated [Ca2+]I Signaling and Alzheimer's Disease-Like Phenotypes of PS1M146V Mice are Attenuated by Decreasing Brain InsP3R-1 Protein Levels" @default.
- W1978363460 doi "https://doi.org/10.1016/j.bpj.2012.11.698" @default.
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