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The Journal of Neuroscience, May 10, 2006, 26(19):5180-5189; doi:10.1523/JNEUROSCI.0739-06.2006

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Neurobiology of Disease
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, and Ian Parker

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697-4550

Correspondence should be addressed to Grace E. Stutzmann, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064. Email: grace.stutzmann{at}rosalindfranklin.edu

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 Ca²⁺ 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 [Ca²⁺] 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.

Key words: Alzheimer; ryanodine receptor; calcium [Ca]; cortex; imaging; inositol trisphosphate; age; presenilin; -amyloid

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Received Dec. 12, 2005; revised March 27, 2006; accepted March 30, 2006.

Correspondence should be addressed to Grace E. Stutzmann, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064. Email: grace.stutzmann{at}rosalindfranklin.edu

This article has been cited by other articles:

				N. Galeotti, A. Quattrone, E. Vivoli, M. Norcini, A. Bartolini, and C. Ghelardini Different involvement of type 1, 2, and 3 ryanodine receptors in memory processes Learn. Mem., April 25, 2008; 15(5): 315 - 323. [Abstract] [Full Text] [PDF]

				G. E. Stutzmann The Pathogenesis of Alzheimers Disease Is It a Lifelong "Calciumopathy"? Neuroscientist, October 1, 2007; 13(5): 546 - 559. [Abstract] [PDF]

				G. E STUTZMANN, I. SMITH, A. CACCAMO, S. ODDO, I. PARKER, and F. LAFERLA Enhanced Ryanodine-Mediated Calcium Release in Mutant PS1-Expressing Alzheimer's Mouse Models Ann. N.Y. Acad. Sci., February 1, 2007; 1097(1): 265 - 277. [Abstract] [Full Text] [PDF]

				C. Supnet, J. Grant, H. Kong, D. Westaway, and M. Mayne Amyloid-beta-(1-42) Increases Ryanodine Receptor-3 Expression and Function in Neurons of TgCRND8 Mice J. Biol. Chem., December 15, 2006; 281(50): 38440 - 38447. [Abstract] [Full Text] [PDF]

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