Calcium dysregulation in Alzheimer's disease: From mechanisms to therapeutic opportunities

Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province 266071, China.
Progress in Neurobiology (Impact Factor: 9.99). 09/2009; 89(3):240-55. DOI: 10.1016/j.pneurobio.2009.07.009
Source: PubMed


Calcium is involved in many facets of neuronal physiology, including activity, growth and differentiation, synaptic plasticity, and learning and memory, as well as pathophysiology, including necrosis, apoptosis, and degeneration. Though disturbances in calcium homeostasis in cells from Alzheimer's disease (AD) patients have been observed for many years, much more attention was focused on amyloid-beta (Abeta) and tau as key causative factors for the disease. Nevertheless, increasing lines of evidence have recently reported that calcium dysregulation plays a central role in AD pathogenesis. Systemic calcium changes accompany almost the whole brain pathology process that is observed in AD, including synaptic dysfunction, mitochondrial dysfunction, presenilins mutation, Abeta production and Tau phosphorylation. Given the early and ubiquitous involvement of calcium dysregulation in AD pathogenesis, it logically presents a variety of potential therapeutic targets for AD prevention and treatment, such as calcium channels in the plasma membrane, calcium channels in the endoplasmic reticulum membrane, Abeta-formed calcium channels, calcium-related proteins. The review aims to provide an overview of the current understanding of the molecular mechanisms involved in calcium dysregulation in AD, and an insight on how to exploit calcium regulation as therapeutic opportunities in AD.

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    • "Similar data were reported by Palop et al. (2003), with a marked reduction in CB protein levels in human patients, as well as in rodent models of AD and by Iritani et al. (2001). These data suggest that calbindin decline occurs when there are high levels of Aβ in the hippocampus (Wang et al., 2003; Yu et al., 2009). Supporting this notion, Popović et al. (2008) observed preservation of CB-IR in the most caudal part of molecular and granular layers of the DG in APPswe/PS1dE9 mice coinciding with a decrease in Aβ deposition. "
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    ABSTRACT: The pathogenesis of Alzheimer Disease (AD) is characterized by accumulation of β-amyloid protein in the brain (in both soluble and insoluble forms) and by the presence of intracellular neurofibrillary tangles (NFTs), leading to neurotoxicity. The exact mechanisms whereby Aβ triggers brain alterations are unclear. However, accumulating evidence suggests that a deregulation of Ca(2+) signaling may play a major role in disease progression. Calcium-buffering proteins, including calbindin-D28K (CB), calretinin (CR) and parvalbumin (PV), may offer neuroprotection by maintaining calcium homeostasis. Although marked reductions in these proteins have been observed in the brains of mice and humans with AD, their contribution to AD pathology remains unclear. The aim of the present study was to analyze distribution patterns of CB(+,) CR(+) and PV(+) interneurons in different areas of the hippocampus, a brain region that is severely affected in AD. A transgenic knock-in APPswe/PS1dE9 mouse model of familial AD was used. The data were obtained from the brains of 3- and 12- month-old animals. These ages roughly correspond to an early mature adult (prior to clinical manifestations) and a late middle-age (clinical symptoms readily detectable) phase in human AD patients. Immunostaining revealed increases in CB and PV immunoreactivity (IR) in hippocampus of 3-month-old transgenic mice, compared to wild-type animals. Possibly, these proteins are upregulated in an attempt to control cellular homeostasis and synaptic plasticity. However, the pattern of CB-IR was reversed in 12-month-old animals, potentially indicating a loss of cellular capacity to respond to pathophysiological processes. In addition, at this age, a noticeable increase in PV-IR was observed, suggesting the presence of hippocampal network hyperactivity in older AD-like mice. Our results indicate that CaBP(+) neuronal subpopulations play a role in adult neurogenesis and in AD pathology, particularly at early disease stages, suggesting that these neurons may serve as potential predictors of future AD in non-demented individuals. Copyright © 2015. Published by Elsevier Inc.
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    • "Not only during common aging but also in AD, calcium dysregulation is a primary event that precedes the early onset of cognitive decline, which is later manifested into neurodegenerative phase of AD patients ( Mattson and Chan, 2001 ; Yu et al., 2009 ). As calcium signaling is implicated in many processes, especially synaptic plasticity , learning, and memory, it is palpable that any mild disturbances in calcium homeostasis will be unfavorable for accurate signaling. "
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    ABSTRACT: Abstract The universality and vitality of calcium ions are implicit from its diverse physiological functions, from regulation of enzymes to synaptic plasticity and memory. However, overloading of these ions could result in life-threatening degenerative disorders. Calcium channels, which are involved in the transport of calcium ions, are targeted and blocked to prevent its overload, favoring vascular relaxation. Besides this primary action, calcium channel blockers (CCBs) also genuinely exhibit cognitive-enhancing abilities and reduce the risk of dementia, especially of Alzheimer's type. Alzheimer's disease (AD) is triggered by the disruption of calcium homeostasis, which underlies the observed progressive cognitive decline that occurs in this neurodegenerative disorder. Fortunately, CCB is expected to offer neuroprotection and additionally demonstrate antiamyloid, antitau, antiphospholipase, antiplatelet, antioxidant, and anti-inflammatory activity, a solitary solution to all the subcellular physiological complications that are observed in AD. Therefore, the aim of this review was to unearth the prospective of CCB against cognitive frailty with a sole purpose of elucidating CCB as cognitive enhancers, which could find its use as a drug in prevention or treatment of AD.
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    • "demonstrated, in another brain EC line, that ER stress increases intracellular Ca 2+ levels [47]. The release of Ca 2+ from ER and consequent increase in cytosolic Ca 2+ levels can activate pathways that culminate in apoptosis [62] [63] [64]. "
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    ABSTRACT: Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. Finally, Aβ1-40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration.
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