Alzheimer's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Alzheimer's Disease, including details on diagnosis, memory loss, heredity, treatment, medication.

Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1.

Nelson O, Tu H, Lei T, Bentahir M, de Strooper B, Bezprozvanny I

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

Mutations in presenilins are responsible for approximately 40% of all early-onset familial Alzheimer disease (FAD) cases in which a genetic cause has been identified. In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD). Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by gamma-secretase. Recently, we discovered that presenilins also function as passive ER Ca(2+) leak channels. Here we used planar lipid bilayer reconstitution assays and Ca(2+) imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca(2+) leak function of 6 FAD-linked PS1 mutants and 3 known FTD-associated PS1 mutants. We discovered that L166P, A246E, E273A, G384A, and P436Q FAD mutations in PS1 abolished ER Ca(2+) leak function of PS1. In contrast, A79V FAD mutation or FTD-associated mutations (L113P, G183V, and Rins352) did not appear to affect ER Ca(2+) leak function of PS1 in our experiments. We validated our findings in Ca(2+) imaging experiments with primary fibroblasts obtained from an FAD patient possessing mutant PS1-A246E. Our results indicate that many FAD mutations in presenilins are loss-of-function mutations affecting ER Ca(2+) leak activity. In contrast, none of the FTD-associated mutations affected ER Ca(2+) leak function of PS1, indicating that the observed effects are disease specific. Our observations are consistent with the potential role of disturbed Ca(2+) homeostasis in Alzheimer disease pathogenesis.

Published 3 May 2007 in J Clin Invest, 117(5): 1230-9.
Full-text of this article is available online (may require subscription).

© 2004-2008 Alzheimer's Disease Research Today. All Rights Reserved.