P3–220: Test of PI3K/Akt signaling hypothesis for mechanism of AD using unique PS1 FAD mutations that do not affect Aβ42 production
Year: 2006
Type: article
Abstract: The PI3K/Akt signaling pathway is of critical importance for the transmission of cell survival signals in a wide range of cell types including neurons. We recently reported that PS1 promotes cadherin–induced activation of Akt and Akt–dependent phosphorylation/inactivation of both glycogen synthase kinase–3 (GSK–3) isoforms, and inhibits GSK–3–dependent tau phosphorylation and apoptotic caspase–3. Using unique PS1 FAD mutants, V82L, L250S and C263R, that may not affect Aβ42 production, test our hypothesis that PS1 FAD mutations compromise Akt cell survival signaling pathway to result in neurodegeneration independently of Aβ42 production. Measure Aβ42 production by ELISA and Western blotting and Akt/GSK–3/tau phosphorylations and caspase activation by Western blotting in various cell lines and primary neurons transduced with PS1 FAD mutants, V82L, L250S and C263R. Although PS1 FAD mutations M146L, E280A and G384A gave an increase in Aβ42 production comparing with PS1 wild type, V82L, L250S and C263R did not significantly increase in Aβ42 production. However, all these mutations interfered with Akt phosphorylation. PS1 FAD mutations affect Akt cell survival signaling and may promote AD neuropathology independent of Aβ42 production.
Source: Alzheimer s & Dementia
Institution: Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2746523762