Age-dependent changes in multiple Ca2+-related electrophysiological processes in the hippocampus appear to be consistent biomarkers of aging, and several also correlate with cognitive decline. These findings have led to the hypothesis that a common mechanism of Ca2+ dyshomeostasis underlies aspects of aging-dependent brain impairment. However, some key predictions of this view remain untested, including that multiple Ca2+-related biomarkers should emerge concurrently during aging and their onset should also precede/coincide with initial signs of cognitive decline. Moreover, blocking a putative common source of dysregulated Ca2+ should eliminate aging differences. Here, we tested these predictions using combined electrophysiological, imaging, and pharmacological approaches in CA1 neurons to determine the ages of onset (across 4-, 10-, 12-, 14-, and 23-month-old F344 rats) of several established biomarkers, including the increases in the slow afterhyperpolarization, spike accommodation, and [Ca2+]i rise during repetitive synaptic stimulation. In addition, we tested the hypothesis that altered Ca2+-induced Ca2+ release (CICR) from ryanodine receptors, which can be triggered by L-type Ca2+ channels, provides a common source of dysregulated Ca2+ in aging. Results showed that multiple aging biomarkers were first detectable at about the same age (12 months of age; approximately midlife), sufficiently early to influence initial cognitive decline. Furthermore, selectively blocking CICR with ryanodine slowed the Ca2+ rise during synaptic stimulation more in aged rat neurons and, notably, reduced or eliminated aging differences in the biomarkers. Thus, this study provides the first evidence that altered CICR plays a role in driving the early and simultaneous emergence in hippocampus of multiple Ca2+-related biomarkers of aging.
"Hence, increased activity of Ca v 1.2 L-type voltage-gated Ca 2+ channels (VGCCs) has been reported in aged hippocampal neurons (Porter et al., 1997; Thibault et al., 2001). In parallel, increased ryanodine receptor-dependent Ca 2+ release from internal stores has been observed (Liu et al., 2014), possibly via enhanced Ca 2+ -induced Ca 2+ release (CICR) as a consequence of increased Ca 2+ influx through L-type channels (Gant et al., 2006). Additionally , decreased plasma membrane Ca 2+ -ATPase activity and Ca 2+ extrusion (Michaelis et al., 1996), as well as diminished Ca 2+ buffering capacity of the aged neuron has been reported (Murchison & Griffith, 1999; Murchison et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: Alteration of intracellular calcium (Ca(2+) ) homeostasis has emerged as an underlying mechanism of neurodegenerative diseases (Marambaud et al., 2009). Within neurons, calcium ions (Ca(2+) ) represent an essential signaling molecule, responsible for regulating a large number of diverse cellular functions including membrane excitability, synaptic transmission, gene expression, synaptogenesis, cell death and survival, but also cellular processes underlying learning and memory (Berridge, 1998). In order to make use of and to regulate the amplitude, duration, and subcellular localization of the Ca(2+) signal, nerve cells have developed an extremely complex machinery, the so-called "Ca(2+) signaling toolkit" (Berridge et al., 2000). It includes ion channels, pumps, and exchangers both in the plasma membrane and in the membranes of intracellular organelles, but also Ca(2+) binding proteins and transcriptional factors that together coordinate neuronal Ca(2+) signaling and homeostasis (Brini et al., 2014). Whereas the molecular mechanisms responsible for alterations of neuronal Ca(2+) signaling in the aging brain are not clearly understood, numerous studies have reported age-related changes in the expression and/or activity of some of the key players of the Ca(2+) machinery, often associated with decreased synaptic plasticity, and in some cases with progressive neuronal loss. Hence, increased activity of Cav 1.2 L-type voltage-gated Ca(2+) channels (VGCCs) has been reported in aged hippocampal neurons (Porter et al., 1997) (Thibault et al., 2001). In parallel, increased ryanodine receptor-dependent Ca(2+) release from internal stores has been observed (Liu et al., 2014), possibly via enhanced Ca(2+) -induced Ca(2+) release (CICR) as a consequence of increased Ca(2+) influx through L-type channels (Gant et al., 2006). Additionally, decreased plasma membrane Ca(2+) -ATPase activity and Ca(2+) extrusion (Michaelis et al., 1996), as well as diminished Ca(2+) buffering capacity of the aged neuron has been reported (Murchison and Griffith, 1999, Murchison et al., 2004). A recent study by Zanos and colleagues (Zanos et al., 2015), reported in this issue of European Journal of Neuroscience, examined the specific contribution of Cav 1.2 channels in aging-associated cognitive decline. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
European Journal of Neuroscience 08/2015; DOI:10.1111/ejn.13017 · 3.18 Impact Factor
"This amplified CICR through RyR leads to apoptosis, necrotic cell death, and finally massive cell death in brain. In fact, CICR through RyR in the hippocampus increases during brain aging ; however, the levels of RyR expression do not change in brain during aging in normal rats . This suggests that certain regulatory molecules that control the function of RyR, such as Snapin, could lead to the amplification of CICR through RyR during aging. "
[Show abstract][Hide abstract] ABSTRACT: To identify critical host factors necessary for human immunodeficiency virus 1 (HIV-1) replication, large libraries of short-peptide-aptamers were expressed retrovirally. The target of one inhibitor peptide, Pep80, identified in this screen was determined to be Snapin, a protein associated with the soluble N-ethyl maleimide sensitive factor adaptor protein receptor (SNARE) complex that is critical for calcium-dependent exocytosis during neurotransmission. Pep80 inhibited Ca(2+) release from intracellular stores and blocked downstream signaling by direct interruption of the association between Snapin and an intracellular calcium release channel, the ryanodine receptor (RyR). NFAT signaling was preferentially abolished by Pep80. Expression of Snapin overcame Pep80-mediated inhibition of Ca(2+)/NFAT signaling and HIV-1 replication. Furthermore, Snapin induced HIV-1 replication in primary CD4(+) T cells. Thus, through its interaction with RyR, Snapin is a critical regulator of Ca(2+) signaling and T cell activation. Use of the genetically selected intracellular aptamer inhibitors allowed us to define unique mechanisms important to HIV-1 replication and T cell biology.
PLoS ONE 10/2013; 8(10):e75297. DOI:10.1371/journal.pone.0075297 · 3.23 Impact Factor
"The mechanism underlying these unique clinical and pathological phenotypes is unknown. It is well established that Ca2+ release from intracellular stores is increased in both sporadic and familial AD [171-173], and thus it is proposed that the disturbed Ca2+ regulation in FAD is correlated with CWP [174,175]. Over 20 PS1 mutations have been analyzed and though all PS1 mutations show increased Aβ42/40 ratio, their effects on calcium signaling are various. "
[Show abstract][Hide abstract] ABSTRACT: Presenilins (PSs) are the catalytic core of gamma-secretase complex. However, the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive. Here we review the general biology and mechanism of gamma-secretase and focus on the catalytic components -- presenilins and their biological functions and contributions to the AD pathogenesis. The functions of presenilins are divided into gamma-secretase dependent and gamma-secretase independent ones. The gamma-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing of APP and Notch; the gamma-secretase independent functions of presenilins include stabilizing beta-catenin in Wnt signaling pathway, regulating calcium homeostasis and their interaction with synaptic transmission.
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