Enhanced ryanodine receptor recruitment contributes to Ca²⁺ disruptions in young, adult, and aged Alzheimer's disease mice

Neuronal Ca²⁺ signaling through inositol triphosphate receptors (IP₃R) and ryanodine receptors (RyRs) must be tightly regulated to maintain cell viability, both acutely and over a lifetime. Exaggerated intracellular Ca²⁺ levels have been associated with expression of Alzheimer's disease (AD) mutations in young mice, but little is known of Ca ²⁺ dysregulations during normal and pathological aging processes. Here, we used electrophysiological recordings with two-photon imaging to study Ca²⁺ signaling in nontransgenic (NonTg) and several AD mouse models (PS1_KI, 3xTg-AD, and APP_SweTau_P301L) at young (6 week), adult (6 months), and old (18 months) ages. At all ages, the PS1 _KI and 3xTg-AD mice displayed exaggerated endoplasmic reticulum (ER) Ca²⁺ signals relative to NonTg mice. The PS1 mutation was the predominant "calciopathic" factor, because responses in 3xTg-AD mice were similar to PS1_KI mice, and APP_SweTau_P301L mice were not different from controls. In addition, we uncovered powerful signaling interactions and differences between IP₃R- and RyR-mediated Ca²⁺ components in NonTg and AD mice. In NonTg mice, RyR contributed modestly to IP₃-evoked Ca²⁺, whereas the exaggerated signals in 3xTg-AD and PS1_KI mice resulted primarily from enhanced RyR-Ca²⁺ release and were associated with increased RyR expression across all ages. Moreover, IP₃-evoked membrane hyperpolarizations in AD mice were even greater than expected from exaggerated Ca²⁺ signals, suggesting increased coupling efficiency between cytosolic [Ca ²⁺] and K⁺ channel regulation. We conclude that lifelong ER Ca²⁺ disruptions in AD are related to a modulation of RyR signaling associated with PS1 mutations and represent a discrete "calciumopathy," not merely an acceleration of normal aging.