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: 3.51). 06/2011; 50(3):303-9. DOI: 10.1016/j.ceca.2011.05.013
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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, Oct 09, 2015
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    • "In addition to this function, presenilins directly or indirectly regulate the trafficking and metabolism of select membrane proteins in neurons [108]. Studies in several models have shown that presenilins play roles in synaptic function [109, 110], learning and memory [111], neuronal survival in the adult brain, regulation of calcium homeostasis [112, 113], and presynaptic neurotransmitter release [114]. PS1 function loss has been reported to inhibit normal migratory neuronal trajectories during neurodevelopment [115]. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia in elderly adults. It is estimated that 10% of the world's population aged more than 60-65 years could currently be affected by AD, and that in the next 20 years, there could be more than 30 million people affected by this pathology. One of the great challenges in this regard is that AD is not just a scientific problem; it is associated with major psychosocial and ethical dilemmas and has a negative impact on national economies. The neurodegenerative process that occurs in AD involves a specific nervous cell dysfunction, which leads to neuronal death. Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer's disease and the association between some of these mutations with both oxidative damage and the development of the pathology.
    Oxidative Medicine and Cellular Longevity 01/2014; 2014(10):375968. DOI:10.1155/2014/375968 · 3.36 Impact Factor
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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 · 2.65 Impact Factor
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