title: Ca2+ influx through store-operated Ca2+ channels reduces Alzheimer disease β-amyloid peptide secretion.
abstract: Alzheimer disease (AD), the leading cause of dementia, is characterized by the accumulation of β-amyloid peptides (Aβ) in senile plaques in the brains of affected patients. Many cellular mechanisms are thought to play important roles in the development and progression of AD. Several lines of evidence point to the dysregulation of Ca(2+) homeostasis as underlying aspects of AD pathogenesis. Moreover, direct roles in the regulation of Ca(2+) homeostasis have been demonstrated for proteins encoded by familial AD-linked genes such as PSEN1, PSEN2, and APP, as well as Aβ peptides. Whereas these studies support the hypothesis that disruption of Ca(2+) homeostasis contributes to AD, it is difficult to disentangle the effects of familial AD-linked genes on Aβ production from their effects on Ca(2+) homeostasis. Here, we developed a system in which cellular Ca(2+) homeostasis could be directly manipulated to study the effects on amyloid precursor protein metabolism and Aβ production. We overexpressed stromal interaction molecule 1 (STIM1) and Orai1, the components of the store-operated Ca(2+) entry pathway, to generate cells with constitutive and store depletion-induced Ca(2+) entry. We found striking effects of Ca(2+) entry induced by overexpression of the constitutively active STIM1(D76A) mutant on amyloid precursor protein metabolism. Specifically, constitutive activation of Ca(2+) entry by expression of STIM1(D76A) significantly reduced Aβ secretion. Our results suggest that disruptions in Ca(2+) homeostasis may influence AD pathogenesis directly through the modulation of Aβ production.
authors.affiliation: From the Departments of Neurobiology, Neurology, and Pathology and.
authors.forename: William
authors.initials: W
authors.lastname: Zeiger
authors.forename: Kulandaivelu S
authors.initials: KS
authors.lastname: Vetrivel
authors.forename: Virginie
authors.initials: V
authors.lastname: Buggia-Prévot
authors.forename: Phuong D
authors.initials: PD
authors.lastname: Nguyen
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
authors.forename: Mitchel L
authors.initials: ML
authors.lastname: Villereal
authors.forename: Gopal
authors.initials: G
authors.lastname: Thinakaran
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins / Q000378:metabolism; D000071740:ORAI1 Protein; D000071737:Stromal Interaction Molecule 1
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: Alzheimer Disease; Amyloid; Amyloid Precursor Protein; Calcium Imaging; Calcium Signaling; Orai1; STIM1; Store-operated Calcium Entry; β-Amyloid
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