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

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2006; 26(19):5180-9. DOI: 10.1523/JNEUROSCI.0739-06.2006
Source: PubMed


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 (PS1KI, 3xTg-AD, and APPSweTauP301L) at young (6 week), adult (6 months), and old (18 months) ages. At all ages, the PS1KI 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 [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.

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Available from: Grace Stutzmann, Aug 21, 2014
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    • "An increase in RyR-mediated Ca 2+ signalling was also observed in cultured neurones (Smith et al. 2005; Zhang et al. 2010), and in slices from 3xTg-AD mice (bearing mutated genes for APP, PS1, and tau) and from TAS/TPM AD mice (expressing mutant APP and PS1 genes). In these last experiments, RyR-mediated Ca 2+ release was substantially elevated in dendrites, dendritic spines, and somata of both AD strains when compared with non-transgenic controls (Goussakov et al. 2010; Stutzmann et al. 2006). Importantly, aberrant Ca 2+ release was observed in AD mice of all ages, being already present in very young animals, being therefore potentially an early marker for pathology. "
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    ABSTRACT: The most accredited (and fashionable) hypothesis of the pathogenesis of Alzheimer Disease (AD) sees accumulation of β-amyloid protein in the brain (in both soluble and insoluble forms) as a leading mechanism of neurotoxicity. How β-amyloid triggers the neurodegenerative disorder is at present unclear, but growing evidence suggests that a deregulation of Ca(2+) homeostasis and deficient Ca(2+) signalling may represent a fundamental pathogenic factor. Given that symptoms of AD are most likely linked to synaptic dysfunction (at the early stages) followed by neuronal loss (at later and terminal phases of the disease), the effects of β-amyloid have been mainly studied in neurones. Yet, it must be acknowledged that neuroglial cells, including astrocytes, contribute to pathological progression of most (if not all) neurological diseases. Here, we review the literature pertaining to changes in Ca(2+) signalling in astrocytes exposed to exogenous β-amyloid or in astrocytes from transgenic Alzheimer disease animals models, characterized by endogenous β-amyloidosis. Accumulated experimental data indicate deregulation of Ca(2+) homeostasis and signalling in astrocytes in AD, which should be given full pathogenetic consideration. Further studies are warranted to comprehend the role of deficient astroglial Ca(2+) signalling in the disease progression.
    Full-text · Article · Jun 2014 · Reviews of Physiology, Biochemistry and Pharmacology
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    • "Actually, PS may directly alter ER Ca2+ signaling and affect activity and/or expression of many proteins involved in ER Ca2+ signaling deregulation in AD. Several studies showed that PS mutations induce exacerbated IP3R- and RyR- mediated Ca2+ release [67-72], and alter the function of the SERCA pump [73]. This has been documented in fibroblasts isolated from FAD patients, in cellular systems expressing wild type and mutated PS and in hippocampal and cortical neurons of AD mice [67,68,70-72]. "
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    ABSTRACT: Perturbed Endoplasmic Reticulum (ER) calcium (Ca2+) homeostasis emerges as a central player in Alzheimer disease (AD). Accordingly, different studies have reported alterations of the expression and the function of Ryanodine Receptors (RyR) in human AD-affected brains, in cells expressing familial AD-linked mutations on the beta amyloid precursor protein (betaAPP) and presenilins (the catalytic core in gamma-secretase complexes cleaving the betaAPP, thereby generating amyloid beta (Abeta) peptides), as well as in the brain of various transgenic AD mice models. Data converge to suggest that RyR expression and function alteration are associated to AD pathogenesis through the control of: i) betaAPP processing and Abeta peptide production, ii) neuronal death; iii) synaptic function; and iv) memory and learning abilities. In this review, we document the network of evidences suggesting that RyR could play a complex dual "compensatory/protective versus pathogenic" role contributing to the setting of histopathological lesions and synaptic deficits that are associated with the disease stages. We also discuss the possible mechanisms underlying RyR expression and function alterations in AD. Finally, we review recent publications showing that drug-targeting blockade of RyR and genetic manipulation of RyR reduces Abeta production, stabilizes synaptic transmission, and prevents learning and memory deficits in various AD mouse models. Chemically-designed RyR "modulators" could therefore be envisioned as new therapeutic compounds able to delay or block the progression of AD.
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    • "2. Alzheimer's disease as a calciumopathy The etiology of AD is unknown, yet increasing evidence points to altered calcium homeostasis as an early and sustained cellular disease mechanism. While there are many diagnostic features, genetic mutations, and risk factors associated with AD, calcium dysregulation is the common denominator associated with many of them (Berridge, 2013; Bezprozvanny and Mattson, 2008; Chakroborty and Stutzmann, 2011; Stutzmann et al., 2007); and in many cases, precedes the detectable pathology (Chakroborty et al., 2009; Cheung et al., 2010; Chong et al., 2011; Muller et al., 2011; Pratt et al., 2011; Stutzmann et al., 2006; Zhang et al., 2009). As listed above, several channels are implicated in the calcium dyshomeostasis associated with AD (Fig. 1). "
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    ABSTRACT: Calcium ions are versatile and universal biological signaling factors that regulate numerous cellular processes ranging from cell fertilization, to neuronal plasticity that underlies learning and memory, to cell death. For these functions to be properly executed, calcium signaling requires precise regulation, and failure of this regulation may tip the scales from a signal for life to a signal for death. Disruptions in calcium channel function can generate complex multi-system disorders collectively referred to as "calciumopathies" that can target essentially any cell type or organ. In this review, we focus on the multifaceted involvement of calcium signaling in the pathophysiology of Alzheimer's disease, and summarize the various therapeutic options currently available to combat this disease. Detailing the series of disappointing AD clinical trial results on cognitive outcomes, we emphasize the urgency to design alternative therapeutic strategies if synaptic and memory functions are to be preserved. One such approach is to target early calcium channelopathies centrally linked to AD pathogenesis.
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