Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040, United States.
Cell calcium (Impact Factor: 4.21). 06/2011; 50(3):303-9. DOI: 10.1016/j.ceca.2011.05.013
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ABSTRACT Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the 'amyloid hypothesis' of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca(2+)) handling and may contribute to AD pathogenesis, an idea termed the 'calcium hypothesis' of AD. Mutations in presenilin proteins account for the majority of FAD cases. Presenilins function as catalytic subunits of γ-secretase involved in the generation of Aβ peptide. Recently, we discovered that presenilns function as low-conductance, passive ER Ca(2+) leak channels, independent of γ-secretase activity. We further discovered that many FAD mutations in presenilins results in the loss of ER Ca(2+) leak function activity and Ca(2+) overload in the ER. These results provided potential explanation for abnormal Ca(2+) signaling observed in FAD cells with mutations in presenilns. The implications of these findings for understanding AD pathogenesis are discussed in this article.

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Available from: Charlene Supnet, Aug 08, 2015
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    • "Moreover, in transgenic mice modeling AD, increased brain levels of several ER stress markers have been described [30] [31]. The presenilins (PSs, components of the γ-secretase complex present in the ER membrane) function as lowconductance , passive ER Ca 2+ leak channels and, consequently, familial AD-linked PS mutations disturb ER Ca 2+ homeostasis leading to increased susceptibility to activation of UPR and caspase-4-induced apoptosis [19] [32] [33]. Nonetheless, mutant PS1 reduces global ER function since it suppresses the activation of IRE1α, ATF6, and PERK and, as a result, GRP78/BiP is downregulated in PS1 mutant AD patients [19]. "
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    ABSTRACT: Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. Finally, Aβ1-40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration.
    Biochimica et Biophysica Acta 08/2013; DOI:10.1016/j.bbadis.2013.08.007 · 4.66 Impact Factor
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    • "Indeed, recent data indicate that PS's catalytic hydrophilic cavity may constitute a Ca 2+ -conductance pore (Nelson et al. 2011). The existence of distinct forms of γ-secretase in different types of cells, with various forms of PS1, could open the possibility for both structural and functional diversity of the γ-secretase complex (Supnet and Bezprozvanny 2011). In fact, an atypical γ-secretase complex with significantly altered subunit stoichiometry was already detected in hematopoietic cell line (Placanica et al. 2010). "
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    ABSTRACT: Presenilin is a central, catalytic component of the γ-secretase complex which conducts intramembrane cleavage of various protein substrates. Although identified and mainly studied through its role in the development of amyloid plaques in Alzheimer disease, γ-secretase has many other important functions. The complex seems to be evolutionary conserved throughout the Metazoa, but recent findings in plants and Dictyostelium discoideum as well as in archeons suggest that its evolution and functions might be much more diversified than previously expected. In this review, a selective survey of the multitude of functions of presenilins and the γ-secretase complex is presented. Following a brief overview of γ-secretase structure, assembly and maturation, three functional aspects are analyzed: (1) the role of γ-secretase in autophagy and phagocytosis; (2) involvement of the complex in signaling related to endocytosis; and (3) control of calcium fluxes by presenilins.
    Protoplasma 03/2013; 250(5). DOI:10.1007/s00709-013-0494-y · 3.17 Impact Factor
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    • "Ca 2þ dysregulation is one feature to consider in that it emerges during the aging process (Disterhoft and Oh, 2007; Foster, 2007; Thibault et al., 2007), accelerates Ab pathology (Demuro et al., 2010; Itkin et al., 2011), and is integral to multiple feed-forward pathologic cascades in AD (Berridge, 2010; Bezprozvanny, 2009; Camandola and Mattson, 2011; Gibson et al., 2010; Hermes et al., 2010; Stutzmann, 2007). Indeed, presenilin mutations associated with familial AD (FAD) cause profound Ca 2þ signaling exaggerations as one of the earliest, if not the earliest, pathogenic event (Muller et al., 2011a; Stutzmann and Mattson, 2011; Stutzmann et al., 2006; Supnet and Bezprozvanny, 2011) followed by accelerated Ab deposition when combined with mutant APP (Auffret et al., 2010; Lazarov et al., 2006). In vivo studies in mutant APP and presenilin-1 (PS1) transgenic mouse models have suggested associations between Ab plaque proximity and abnormal cellular Ca 2þ in cortex. "
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    ABSTRACT: Alzheimer's disease (AD) is a multifactorial disorder of unknown etiology. Mechanistically, beta amyloid peptides (Aβ) and elevated Ca(2+) have been implicated as proximal and likely interactive features of the disease process. We tested the hypothesis that proximity to Aβ plaque might exacerbate activity-dependent neuronal Ca(2+) signaling in hippocampal pyramidal neurons from APP(SWE)/PS1(M146V) mice. Using combined approaches of whole cell patch clamp recording and 2-photon imaging of neuronal Ca(2+) signals with thioflavin-S plaque labeling in hippocampal slices, we found no correlation between thioflavin-S labeled Aβ plaque proximity and Ca(2+) responses triggered by ryanodine receptor (RyR) activation or action potentials in either dendrites or somata of AD mice, regardless of age. Baseline and RyR-stimulated spontaneous excitatory postsynaptic potentials also showed little difference in relation to Aβ plaque proximity. Consistent with previous studies, RyR-evoked Ca(2+) release in APP(SWE)/PS1(M146V) mice was greater than in nontransgenic controls. Within the soma, RyR-evoked Ca(2+) release was elevated in older APP(SWE)/PS1(M146V) mice compared with younger APP(SWE)/PS1(M146V) mice, but was still independent of plaque proximity. The results indicate that early Ca(2+) signaling disruptions can become yet more severe with age through mechanisms independent of Aβ plaques, suggesting that alternative pathogenic mechanisms might contribute to AD-associated dysfunction.
    Neurobiology of aging 01/2013; 34(6). DOI:10.1016/j.neurobiolaging.2012.12.013 · 4.85 Impact Factor
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