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

Grace E. Stutzmann, Ian Smith, Antonella Caccamo, Salvatore Oddo, Frank M. LaFerla, Ian Parker

Research output: Contribution to journalArticle

223 Scopus citations

Abstract

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 (PS1KI, 3xTg-AD, and APPSweTauP301L) 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 PS1KI mice, and APPSweTauP301L 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 PS1KI 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.

Original languageEnglish (US)
Pages (from-to)5180-5189
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number19
DOIs
StatePublished - Sep 7 2006

Keywords

  • Age
  • Alzheimer
  • Calcium [Ca]
  • Cortex
  • Imaging
  • Inositol trisphosphate
  • Presenilin
  • Ryanodine receptor
  • β-amyloid

ASJC Scopus subject areas

  • Neuroscience(all)

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