Upregulation of the Sarco-Endoplasmic Reticulum Calcium ATPase 1 Truncated Isoform Plays a Pathogenic Role in Alzheimer's Disease.

ABSTRACT: Dysregulation of the Endoplasmic Reticulum (ER) Ca2+ homeostasis and subsequent ER stress activation occur in Alzheimer Disease (AD). We studied the contribution of the human truncated isoform of the sarco-endoplasmic reticulum Ca2+ ATPase 1 (S1T) to AD. We examined S1T expression in human AD-affected brains and its functional consequences in cellular and transgenic mice AD models. S1T expression is increased in sporadic AD brains and correlates with amyloid ? (A?) and ER stress chaperone protein levels. Increased S1T expression was also observed in human neuroblastoma cells expressing Swedish-mutated ?-amyloid precursor protein (?APP) or treated with A? oligomers. Lentiviral overexpression of S1T enhances in return the production of APP C-terminal fragments and A? through specific increases of ?-secretase expression and activity, and triggers neuroinflammation. We describe a molecular interplay between S1T-dependent ER Ca2+ leak, ER stress and ?APP-derived fragments that could contribute to AD setting and/or progression.

SUBMITTER: Bussiere R 

PROVIDER: S-EPMC6953121 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature