In Alzheimer disease (AD), the perturbation of the endoplasmic reticulum (ER) calcium (Ca²⁺) homeostasis has been linked to presenilins, the catalytic core in γ-secretase complexes cleaving the amyloid precursor protein (APP), thereby generating amyloid-β (Aβ) peptides. Here we investigate whether APP contributes to ER Ca²⁺homeostasis and whether ER Ca²⁺could in turn influence Aβ production. We show that overexpression of wild-type human APP (APP₆₉₅), or APP harboring the Swedish double mutation (APP_swe) triggers increased ryanodine receptor (RyR) expression and enhances RyR-mediated ER Ca²⁺release in SH-SY5Y neuroblastoma cells and in APP_swe-expressing (Tg2576) mice. Interestingly, dantrolene-induced lowering of RyR-mediated Ca²⁺release leads to the reduction of both intracellular and extracellular Aβ load in neuroblastoma cells as well as in primary cultured neurons derived from Tg2576 mice. This Aβ reduction can be accounted for by decreased Thr-668-dependent APP phosphorylation and β- and γ-secretases activities. Importantly, dantrolene diminishes Aβ load, reduces Aβ-related histological lesions, and slows down learning and memory deficits in Tg2576 mice. Overall, our data document a key role of RyR in Aβ production and learning and memory performances, and delineate RyR-mediated control of Ca²⁺homeostasis as a physiological paradigm that could be targeted for innovative therapeutic approaches.