Alzheimer Disease: Bezprozvanny I

Bezprozvanny I. · Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. · Sci Signal. · Pubmed #19318622 No free full text.

Abstract: The brains of patients with Alzheimer's disease (AD) contain abundant plaques composed of beta-amyloid (Abeta) peptides. It has been assumed that amyloid plaques and soluble Abeta oligomers induce neuronal pathology in AD; however, the mechanism by which amyloid mediates pathological effects is not clearly understood. In vivo calcium (Ca2+) imaging and array tomography studies with AD mouse models are providing new insights into the changes that occur in brain structure and function as a result of amyloid plaque accumulation. The unexpected lesson from these studies is that amyloid plaques result in both localized and global changes in brain function. The amyloid-induced effects include short-range changes in neuronal Ca2+ concentrations, medium-range changes in neuronal activity and synaptic density, and long-range changes in Ca2+ signaling in astrocytes and induction of intracellular Ca2+ waves spreading through a network of astrocytes. These results have potential implications for understanding synaptic and neuronal network dysfunction in AD brains.

Bezprozvanny I, Mattson MP. · Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Trends Neurosci. · Pubmed #18675468 links to  free full text

Abstract: Perturbed neuronal Ca(2+) homeostasis is implicated in age-related cognitive impairment and Alzheimer's disease (AD). With advancing age, neurons encounter increased oxidative stress and impaired energy metabolism, which compromise the function of proteins that control membrane excitability and subcellular Ca(2+) dynamics. Toxic forms of amyloid beta-peptide (Abeta) can induce Ca(2+) influx into neurons by inducing membrane-associated oxidative stress or by forming an oligomeric pore in the membrane, thereby rendering neurons vulnerable to excitotoxicity and apoptosis. AD-causing mutations in the beta-amyloid precursor protein and presenilins can compromise these normal proteins in the plasma membrane and endoplasmic reticulum, respectively. Emerging knowledge of the actions of Ca(2+) upstream and downstream of Abeta provides opportunities to develop novel preventative and therapeutic interventions for AD.

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. · J Clin Invest. · Pubmed #17431506 links to  free full text

Abstract: 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.

Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I. · Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. · Cell. · Pubmed #16959576 No free full text.

Abstract: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. Mutations in presenilins 1 and 2 (PS1 and PS2) account for approximately 40% of familial AD (FAD) cases. FAD mutations and genetic deletions of presenilins have been associated with calcium (Ca(2+)) signaling abnormalities. We demonstrate that wild-type presenilins, but not PS1-M146V and PS2-N141I FAD mutants, can form low-conductance divalent-cation-permeable ion channels in planar lipid bilayers. In experiments with PS1/2 double knockout (DKO) mouse embryonic fibroblasts (MEFs), we find that presenilins account for approximately 80% of passive Ca(2+) leak from the endoplasmic reticulum. Deficient Ca(2+) signaling in DKO MEFs can be rescued by expression of wild-type PS1 or PS2 but not by expression of PS1-M146V or PS2-N141I mutants. The ER Ca(2+) leak function of presenilins is independent of their gamma-secretase activity. Our data suggest a Ca(2+) signaling function for presenilins and provide support for the "Ca(2+) hypothesis of AD."