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: 5.48). 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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    • "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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    The international journal of biochemistry & cell biology 07/2012; 44(11):1983-6. DOI:10.1016/j.biocel.2012.07.019 · 4.24 Impact Factor
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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.
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