Ryanodine Receptor Blockade Reduces Amyloid-β Load and Memory Impairments in Tg2576 Mouse Model of Alzheimer Disease

In Alzheimer disease (AD), the perturbation of the endoplasmic reticulum (ER) calcium (Ca2+) homeostasis has been linked to presenilins, the catalytic core in gamma-secretase complexes cleaving the amyloid precursor protein (APP), thereby generating amyloid-beta (A beta) peptides. Here we investigate whether APP contributes to ER Ca2+ homeostasis and whether ER Ca2+ could in turn influence A beta production. We show that overexpression of wild-type human APP (APP(695)), 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 APPswe-expressing (Tg2576) mice. Interestingly, dantrolene-induced lowering of RyR-mediated Ca2+ release leads to the reduction of both intracellular and extracellular A beta load in neuroblastoma cells as well as in primary cultured neurons derived from Tg2576 mice. This A beta reduction can be accounted for by decreased Thr-668-dependent APP phosphorylation and beta- and gamma-secretases activities. Importantly, dantrolene diminishes A beta load, reduces A beta-related histological lesions, and slows down learning and memory deficits in Tg2576 mice. Overall, our data document a key role of RyR in A beta 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.