Enhanced Ryanodine Receptor Recruitment Contributes to Ca2+Disruptions in Young, Adult, and Aged Alzheimer's Disease Mice

Abstract

Neuronal Ca 2+signaling through inositol triphosphate receptors (IP 3 R) and ryanodine receptors (RyRs) must be tightly regulated to maintain cell viability, both acutely and over a lifetime. Exaggerated intracellular Ca 2+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 Ca 2+signaling in nontransgenic (NonTg) and several AD mouse models (PS1 KI, 3xTg-AD, and APP Swe Tau 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) Ca 2+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 Swe Tau P301L mice were not different from controls. In addition, we uncovered powerful signaling interactions and differences between IP 3 R- and RyR-mediated Ca 2+components in NonTg and AD mice. In NonTg mice, RyR contributed modestly to IP 3-evoked Ca 2+, whereas the exaggerated signals in 3xTg-AD and PS1 KI mice resulted primarily from enhanced RyR-Ca 2+release and were associated with increased RyR expression across all ages. Moreover, IP 3-evoked membrane hyperpolarizations in AD mice were even greater than expected from exaggerated Ca 2+signals, suggesting increased coupling efficiency between cytosolic [Ca 2+] and K+channel regulation. We conclude that lifelong ER Ca 2+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.