PS2 mutation increases neuronal cell vulnerability to neurotoxicants through activation of caspase-3 by enhancing of ryanodine receptor-mediated calcium release

College of Pharmacy, Chungbuk National University, Chungbuk, Korea.
The FASEB Journal (Impact Factor: 5.04). 02/2006; 20(1):151-3. DOI: 10.1096/fj.05-4017fje;1
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Available from: Do-Young Yoon, Oct 01, 2014
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    • "Moreover, DP5 specifically interacts with Bcl-xl during neuronal apoptosis following exposure to Aβ, and its binding could impair the survival-promoting activities of Bcl-xl [146]. Accordingly, dantrolene treatment protected PC12 cells expressing PS2N141L mutant from death induced by L-glutamate and Aβ toxic peptides [96]. The direct implication of RyR in neuronal death was also proposed by Supnet et al. who showed that suppression of RyR3 expression in TgCRND8 neurons, increased neuronal death [91,147], thus supporting a protective role of RyR in the late stages of AD pathogenesis, at least in this mice model. "
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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.
    Full-text · Article · Jun 2014 · Molecular Neurodegeneration
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    • "Furthermore , we have demonstrated that PS1 influences the structural plasticity of postsynaptic dendritic spines in the somatosensory cortex (Jung et al., 2011). FAD-PS mutations have been shown to increase the neuronal vulnerability to A␤ and glutamate through caspase-3 activation as a result of RyR3 isoform upregulation and enhanced RyR-mediated calcium release in PC12 cells (Lee et al., 2006). Notably, the FAD-PS mediated vulnerability and apoptosis can be normalized by pharmacologically or functionally inhibiting the IP 3 R-CaMKIV-CREB pathway in SH-SY5Y cells (Muller et al., 2011). "
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    ABSTRACT: Mutations in presenilins are responsible for the vast majority of early-onset familial Alzheimer's disease cases. Full-length presenilin structure is composed of nine transmembrane domains which are localized on the endoplasmic reticulum membrane. Upon endoproteolytic cleavage, presenilins assemble into the γ-secretase multiprotein complex and subsequently get transported to the cell surface. There is a wealth of knowledge around the role of presenilins as the catalytic component of γ-secretase, their involvement in amyloid precursor protein processing and generation of neurotoxic β-amyloid species. However recent findings have revealed a wide range of γ-secretase-independent presenilin functions, including involvement in calcium homeostasis. Particularly, familial Alzheimer's disease presenilin mutations have been shown to interfere with the function of several molecular elements involved in endoplasmic reticulum calcium homeostasis. Presenilins modulate the activity of IP(3) and Ryanodine receptor channels, regulate SERCA pump function, affect capacitative calcium entry and function per se as endoplasmic reticulum calcium leak conductance pores.
    Full-text · Article · Jul 2012 · The international journal of biochemistry & cell biology
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    • "The data in cultured neurons indicate that, while in cells from tg mice activation of IP 3 -Rs results in an attenuated Ca 2+ peak, the response to Ry-Rs is increased. It has been demonstrated that in other AD mouse models based on PS mutants, the expression level of Ry-Rs is enhanced compared with wt animals (Lee et al., 2006; Stutzmann et al., 2007). "
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    ABSTRACT: Mutations in amyloid precursor protein (APP), and presenilin-1 and presenilin-2 (PS1 and PS2) have causally been implicated in Familial Alzheimer's Disease (FAD), but the mechanistic link between the mutations and the early onset of neurodegeneration is still debated. Although no consensus has yet been reached, most data suggest that both FAD-linked PS mutants and endogenous PSs are involved in cellular Ca(2+) homeostasis. We here investigated subcellular Ca(2+ ) handling in primary neuronal cultures and acute brain slices from wild type and transgenic mice carrying the FAD-linked PS2-N141I mutation, either alone or in the presence of the APP Swedish mutation. Compared with wild type, both types of transgenic neurons show a similar reduction in endoplasmic reticulum (ER) Ca(2+) content and decreased response to metabotropic agonists, albeit increased Ca(2+) release induced by caffeine. In both transgenic neurons, we also observed a higher ER-mitochondria juxtaposition that favors increased mitochondrial Ca(2+) uptake upon ER Ca(2+) release. A model is described that integrates into a unifying hypothesis the contradictory effects on Ca(2+) homeostasis of different PS mutations and points to the relevance of these findings in neurodegeneration and aging.
    Full-text · Article · Jul 2012 · Aging cell
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