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Here we investigate whether APP contributes to ER Ca<jats:sup>2+<\/jats:sup>homeostasis and whether ER Ca<jats:sup>2+<\/jats:sup>could in turn influence A\u03b2 production. We show that overexpression of wild-type human APP (APP<jats:sub>695<\/jats:sub>), or APP harboring the Swedish double mutation (APP<jats:sub>swe<\/jats:sub>) triggers increased ryanodine receptor (RyR) expression and enhances RyR-mediated ER Ca<jats:sup>2+<\/jats:sup>release in SH-SY5Y neuroblastoma cells and in APP<jats:sub>swe<\/jats:sub>-expressing (Tg2576) mice. Interestingly, dantrolene-induced lowering of RyR-mediated Ca<jats:sup>2+<\/jats:sup>release leads to the reduction of both intracellular and extracellular A\u03b2 load in neuroblastoma cells as well as in primary cultured neurons derived from Tg2576 mice. This A\u03b2 reduction can be accounted for by decreased Thr-668-dependent APP phosphorylation and \u03b2- and \u03b3-secretases activities. Importantly, dantrolene diminishes A\u03b2 load, reduces A\u03b2-related histological lesions, and slows down learning and memory deficits in Tg2576 mice. Overall, our data document a key role of RyR in A\u03b2 production and learning and memory performances, and delineate RyR-mediated control of Ca<jats:sup>2+<\/jats:sup>homeostasis as a physiological paradigm that could be targeted for innovative therapeutic approaches.<\/jats:p>","DOI":"10.1523\/jneurosci.0875-12.2012","type":"journal-article","created":{"date-parts":[[2012,8,22]],"date-time":"2012-08-22T16:34:30Z","timestamp":1345653270000},"page":"11820-11834","source":"Crossref","is-referenced-by-count":235,"title":["Ryanodine Receptor Blockade Reduces Amyloid-\u03b2 Load and Memory Impairments in Tg2576 Mouse Model of Alzheimer Disease"],"prefix":"10.1523","volume":"32","author":[{"given":"B\u00e9n\u00e9dicte","family":"Oul\u00e8s","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Del 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