Calcium and Neurodegeneration

Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
Aging Cell (Impact Factor: 6.34). 07/2007; 6(3):337-50. DOI: 10.1111/j.1474-9726.2007.00275.x
Source: PubMed


When properly controlled, Ca2+ fluxes across the plasma membrane and between intracellular compartments play critical roles in fundamental functions of neurons, including the regulation of neurite outgrowth and synaptogenesis, synaptic transmission and plasticity, and cell survival. During aging, and particularly in neurodegenerative disorders, cellular Ca2+-regulating systems are compromised resulting in synaptic dysfunction, impaired plasticity and neuronal degeneration. Oxidative stress, perturbed energy metabolism and aggregation of disease-related proteins (amyloid beta-peptide, alpha-synuclein, huntingtin, etc.) adversely affect Ca2+ homeostasis by mechanisms that have been elucidated recently. Alterations of Ca2+-regulating proteins in the plasma membrane (ligand- and voltage-gated Ca2+ channels, ion-motive ATPases, and glucose and glutamate transporters), endoplasmic reticulum (presenilin-1, Herp, and ryanodine and inositol triphosphate receptors), and mitochondria (electron transport chain proteins, Bcl-2 family members, and uncoupling proteins) are implicated in age-related neuronal dysfunction and disease. The adverse effects of aging on neuronal Ca2+ regulation are subject to modification by genetic (mutations in presenilins, alpha-synuclein, huntingtin, or Cu/Zn-superoxide dismutase; apolipoprotein E isotype, etc.) and environmental (dietary energy intake, exercise, exposure to toxins, etc.) factors that may cause or affect the risk of neurodegenerative disease. A better understanding of the cellular and molecular mechanisms that promote or prevent disturbances in cellular Ca2+ homeostasis during aging may lead to novel approaches for therapeutic intervention in neurological disorders such as Alzheimer's and Parkinson's diseases and stroke.

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    • "When properly controlled, Ca 2+ fluxes across the plasma membrane and between intracellular compartments where it plays critical roles in fundamental functions of neurons (Mattson 2007). However, deregulation of calcium homeostasis leads to neurodegeneration via complex and diverse mechanisms involved in selective neuronal impairments and death (Mattson 2007). Implication of calcium in many neurodegenerative diseases leading to neurological disorders and cognitive deficits has been documented. "
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    ABSTRACT: Postnatal protein-undernutrition impacts on mental development and cognition in children and can lead to problem with attention and unresponsiveness which compromise children's ability to learn. These behavioral disorders might be due to alteration in calcium homeostasis as calcium plays critical roles in fundamental functions of neuron. The role of low protein diet as well as Se and Zn supplementation on intracellular calcium concentration ([Ca(2+)]i), Ca(2+)-ATPase, Na(+)-K(+)-ATPase, calpain and caspase-3 activities from rat cortex and cerebellum were investigated. Well-fed (WF) and low protein diet-fed (LPDF) rats were given diets containing 16% and 5% casein, respectively, for a period of 10 weeks. Then, the rats were supplemented with Se and Zn at a concentration of 0.15mgL(-1) and 227mgL(-1), respectively, in drinking water for 3 weeks. The results obtained from the study showed a significant increase in [Ca(2+)]i; calpain and caspase-3 activities as well as increase transfer latency in water maze study and reductions in Ca(2+)-ATPase and Na(+)-K(+)-ATPase activities for LPDF rats compared to WF rats. Se and Zn supplementation to LPDF rats reversed the elevation in [Ca(2+)]i, calpain and caspase-3 activities and restored the cognitive deficits and the activities of Ca(2+)-ATPase and Na(+)-K(+)-ATPase. Conclusively, protein-undernutrition results in the accumulation of synaptosomal [Ca(2+)]i and inhibition of calcium transporters presumably via free radical generations and results in cognitive impairment which also probably results from neuronal death in rats through calpain activation and the caspase cascade mechanisms. However, Se and Zn supplementations ameliorated the anomalies observed. Copyright © 2015. Published by Elsevier Ltd.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 03/2015; 43. DOI:10.1016/j.ijdevneu.2015.03.007 · 2.58 Impact Factor
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    • "Oligomers, in particular, modulate ion channel activity/Ca 2 + permeable receptors resulting in excess intracellular Ca 2 + , which in turn seems to further drive amyloid-b production (De Felice et al., 2007; Green et al., 2007; Green and LaFerla, 2008; Renner et al., 2010). The toxicity of amyloid-b is also mediated, at least in part, by increased intracellular calcium, and is prevented by expression of calbindin (Mattson et al., 1991; Guo et al., 1998; Mattson, 2007). The goal of the present experiments was to investigate whether in conjunction with loss of calbindin, and similar to accumulation of amyloid-b in the non-human primate, the human BFCNs display accumulation of amyloid-b in the course of ageing, and in Alzheimer's disease. "
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    ABSTRACT: The mechanisms that contribute to selective vulnerability of the magnocellular basal forebrain cholinergic neurons in neurodegenerative diseases, such as Alzheimer's disease, are not fully understood. Because age is the primary risk factor for Alzheimer's disease, mechanisms of interest must include age-related alterations in protein expression, cell type-specific markers and pathology. The present study explored the extent and characteristics of intraneuronal amyloid-β accumulation, particularly of the fibrillogenic 42-amino acid isoform, within basal forebrain cholinergic neurons in normal young, normal aged and Alzheimer's disease brains as a potential contributor to the selective vulnerability of these neurons using immunohistochemistry and western blot analysis. Amyloid-β1-42 immunoreactivity was observed in the entire cholinergic neuronal population regardless of age or Alzheimer's disease diagnosis. The magnitude of this accumulation as revealed by optical density measures was significantly greater than that in cortical pyramidal neurons, and magnocellular neurons in the globus pallidus did not demonstrate a similar extent of amyloid immunoreactivity. Immunoblot analysis with a panel of amyloid-β antibodies confirmed accumulation of high concentration of amyloid-β in basal forebrain early in adult life. There was no age- or Alzheimer-related alteration in total amyloid-β content within this region. In contrast, an increase in the large molecular weight soluble oligomer species was observed with a highly oligomer-specific antibody in aged and Alzheimer brains when compared with the young. Similarly, intermediate molecular weight oligomeric species displayed an increase in aged and Alzheimer brains when compared with the young using two amyloid-β42 antibodies. Compared to cortical homogenates, small molecular weight oligomeric species were lower and intermediate species were enriched in basal forebrain in ageing and Alzheimer's disease. Regional and age-related differences in accumulation were not the result of alterations in expression of the amyloid precursor protein, as confirmed by both immunostaining and western blot. Our results demonstrate that intraneuronal amyloid-β accumulation is a relatively selective trait of basal forebrain cholinergic neurons early in adult life, and increases in the prevalence of intermediate and large oligomeric assembly states are associated with both ageing and Alzheimer's disease. Selective intraneuronal amyloid-β accumulation in adult life and oligomerization during the ageing process are potential contributors to the degeneration of basal forebrain cholinergic neurons in Alzheimer's disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 03/2015; 138(6). DOI:10.1093/brain/awv024 · 9.20 Impact Factor
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    • "In addition, impaired neuronal bioenergetics and inflammation-like processes involving glial and immune cells occur during normal brain ageing and are exacerbated in neurodegenerative disorders such as Alzheimer's disease (Kapogiannis and Mattson, 2011; Lynch, 2010; Rao et al., 2012). Oxidative stress, metabolic compromise and neuroinflammation may render synapses vulnerable to degeneration by promoting excessive calcium influx and accumulation in synapses (Foster, 2007; Mattson, 2007). A general mechanism whereby dietary energy restriction can mitigate age-related structural and functional deficits in synapses is by triggering adaptive cellular stress responses including the up-regulation of neurotrophic factor signaling pathways, protein chaperones and antioxidant enzymes (Arumugam et al., 2010; Stranahan and Mattson, 2012). "
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    ABSTRACT: Impaired synaptic plasticity is implicated in the functional decline of the nervous system associated with ageing. Understanding the structure of ageing synapses is essential to understanding the functions of these synapses and their role in the ageing nervous system. In this review, we summarize studies on ageing synapses in vertebrates and invertebrates, focusing on changes in morphology and ultrastructure. We cover different parts of the nervous system, including the brain, the retina, the cochlea, and the neuromuscular junction. The morphological characteristics of aged synapses could shed light on the underlying molecular changes and their functional consequences.
    Ageing research reviews 03/2014; 14(1). DOI:10.1016/j.arr.2014.01.003 · 4.94 Impact Factor
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