Journal
CELLS
Volume 8, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/cells8121539
Keywords
Alzheimer disease; amyloid beta; amyloid precursor protein; BACE1; C83; C99; endoplasmic reticulum stress; neuroinflammation; truncated isoform of the sarco-endoplasmic reticulum Ca2+ ATPase 1 (S1T)
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Funding
- Fondation Vaincre Alzheimer [13737]
- Fondation pour la Recherche Medicale [DEQ20071210550]
- LABEX (excellence laboratory, program investment for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer's disease)
- University Hospital Federation (FHU) OncoAge
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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 beta (A beta) and ER stress chaperone protein levels. Increased S1T expression was also observed in human neuroblastoma cells expressing Swedish-mutated beta-amyloid precursor protein (beta APP) or treated with A beta oligomers. Lentiviral overexpression of S1T enhances in return the production of APP C-terminal fragments and A beta through specific increases of beta-secretase expression and activity, and triggers neuroinflammation. We describe a molecular interplay between S1T-dependent ER Ca2+ leak, ER stress and beta APP-derived fragments that could contribute to AD setting and/or progression.
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