Amyloid-β promotes calcium influx and neurodegeneration via stimulation of L voltage-sensitive calcium channels rather than NMDA channels in cultured neurons

Ho, Rebecca; Ortiz, Daniela; Shea, Thomas B.

doi:10.3233/jad-2001-3507

Cited by 50 publications

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“…Using calciumsensitive dyes, several groups showed that Aβ25-35 increases intracellular calcium levels, and different classical calcium antagonists prevent this increase in vitro (Silei et al, 1999;Yagami et al, 2002;Fu et al, 2006). Ho et al examined Aβ-mediated increases of the intracellular calcium load in cultured cortical neurons and showed that it was sensitive to nimopridine (Ho et al, 2001). Based on the assumption that classical calcium antagonists block L-type calcium channels, the authors concluded that Aβ enhances calcium flux through these channels.…”

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confidence: 99%

Calcium channel blockers and dementia

Nimmrich

Eckert

2013

British J Pharmacology

128

104

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Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid-β. Recent studies suggest that soluble forms facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid-β-induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof-of-concept studies are now available. AbbreviationsAβ, amyloid-β; AD, Alzheimer's disease; APP, amyloid precursor protein; LTP, long-term potentiation; VaD, vascular dementia; VGCC, voltage-gated calcium channel IntroductionDementia affects 7% of the population over the age of 65, and then progressively increases with age Rocca et al., 1991). Alzheimer's disease (AD) is the leading cause of dementia, followed by vascular dementia (VaD). AD is characterized by three neuropathological hallmarks: extracellular aggregates of amyloid-β (Aβ) peptide (amyloid plaques), neurofibrillary tangles and synaptic loss (Bell and Cuello, 2006). According to the amyloid cascade hypothesis, overproduction of the hydrophobic peptide Aβ 1-42 is the basis for AD pathology (Hardy and Higgins, 1992).Aggregation of Aβ 1-42 is thought to occur in several steps via fibrils, which are finally deposited as amyloid plaques. It was suggested that an alternative pathway leads to the generation of stable oligomeric aggregates, Aβ oligomers (Gellermann et al., 2008;Yu et al., 2009b), which are considered to mediate the toxic Aβ effects (Hardy and Selkoe, 2002). Different forms of Aβ oligomers can be generated synthetically (e.g. Stine et al., 2003; Barghorn et al., 2005) or are harvested from cell lines (Walsh et al., 2002). These preparations were tested in vitro and in animal models, and the results lead to the generally accepted view that Aβ oligomers specifically disturb synaptic function . Constant impairment of neurotransmission leads to a retraction of synapses, which is then evident in the autopsy of AD brains (for a review, see Nimmrich a...

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confidence: 99%

Calcium channel blockers and dementia

Nimmrich

Eckert

2013

British J Pharmacology

128

104

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“…But if there is only one pathological pathway of dangerous increase of cytosolic Ca 2+ , in this case, it would be possible to block this pathway and prevent development of disease. For example, it was reported that h-amyloid peptide activated voltage-sensitive Ca 2+ channel (VSCC) (Ho et al, 2001). If it is only pathway, in such case CCB may prevent development of AD.…”

Section: Discussionmentioning

confidence: 99%

Divergent role of calcium on Aβ- and MPTP-induced cell death in SK-N-SH neuroblastoma

Lee¹,

Tsai

Yeh³

et al. 2006

Life Sciences

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“…These diseases may be ameliorated or prevented by the removal of harmful cells (Feske, 2007;Liossis et al, 1996;Saido et al, 1994;Saito et al, 1993;Tsuji et al, 1998;Lee et al, 1991;Hajimohammadreza et al, 1997;Saatman et al, 1996;Nakagawa et al, 2000). Indeed, amyloid β induces calcium influx into neurons which in turn can cause neurotoxicity (apoptosis) that results in Alzheimer's disease (Ho et al, 2001). Milk fat globule epidermal growth-factor 8 (MFG-E8), which initially attaches to PS on apoptotic cells and then forms a link with phagocytes to initiate or augment phagocytosis (Hanayama et al, 2002), may prevent Alzheimer's disease in the brain via microglia that aid in clearing amyloid β-induced apoptotic neurons (Fuller and Van Eldik, 2008).…”

Section: Discussionmentioning

confidence: 99%

Macrophage Recognition of Cells with Elevated Calcium Is Mediated by Carbohydrate Chains of CD43

Miki

Oguri

Hirano

et al. 2013

Cell Struct. Funct.

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ABSTRACT. Macrophages remove deteriorating cells (those undergoing apoptosis and oxidation) via poly-Nacetyllactosaminyl chains on CD43 caps, a major cell-surface glycoprotein. Unusually high intracellular calcium levels are also deteriorating for cells and tissue. Here we artificially elevated calcium levels in cells and examined the mechanism by which this elevation was resolved by macrophages. Results showed that treatment with the calcium ionophore A23187 and ionomycin induces capping of CD43 on Jurkat cells, which are subsequently recognized and phagocytosed by macrophages, indicating that macrophages regard cells with elevated calcium as targets for removal. Further tests showed that A23187-and ionomycin-treated Jurkat cells did not induce apoptotic changes such as DNA fragmentation or phosphatidylserine expression, indicating that these cells were removed despite still being viable. Jurkat cells pretreated with anti-CD43 antibody or those with poly-Nacetyllactosaminyl chains containing oligosaccharides inhibited macrophage binding, indicating that macrophages recognize the poly-N-acetyllactosaminyl chains on CD43. Binding was also inhibited by treating macrophages with anti-nucleolin antibody, indicating that recognition occurs through nucleolin, a cell-surface receptor. Further, nucleolin-transfected HEK293 cells bound A23187-treated cells, and this binding was inhibited by in the presence of oligosaccharides. Taken together, these results show that elevated calcium levels induce CD43 capping, and macrophages remove the cells if their nucleolin receptors can bind to the poly-Nacetyllactosaminyl chains of capped CD43.

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Amyloid-β promotes calcium influx and neurodegeneration via stimulation of L voltage-sensitive calcium channels rather than NMDA channels in cultured neurons

Cited by 50 publications

References 0 publications

Calcium channel blockers and dementia

Calcium channel blockers and dementia

Divergent role of calcium on Aβ- and MPTP-induced cell death in SK-N-SH neuroblastoma

Macrophage Recognition of Cells with Elevated Calcium Is Mediated by Carbohydrate Chains of CD43

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