Ca2+ dysregulation in the endoplasmic reticulum related to Alzheimer’s disease: A review on experimental progress and computational modeling

Liang, Jingyi; Kulasiri, Don; Samarasinghe, Sandhya

doi:10.1016/j.biosystems.2015.05.003

Cited by 26 publications

(25 citation statements)

References 187 publications

(248 reference statements)

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“…There is a general thesis that oligomeric extra- and intracellular deposits of Aβ, forming high-permeability non regulated Ca-channels in cell membranes including mitochondria and endoplasmic reticulum, are the main cause of neuronal injury in the course of AD [131, 132]. Neurotoxic properties of Aβ have been demonstrated in several experimental paradigms [122, 133, 134].…”

Section: Acetyl-coa and Amyloid β Neurotoxicitymentioning

confidence: 99%

“…High conductance Ca-channels formed by Aβ oligomers in cell membranes, activated influx of extracellular Ca thereby impairing energy metabolism, inhibiting PDHC and KDHC as well as activating PTP and release of pro apoptotic peptides, and sirtuin-linked catabolic pathways (Fig. 1) [132, 138–141]. Accumulation of extracellular Aβ aggravated suppressive effects of NGF mediated by p75 receptors abundantly expressed in cultured septal neuronal cells with high expression of cholinergic phenotype, yielding different suppressive and neurotoxic reactions [47, 71, 142].…”

Section: Acetyl-coa and Amyloid β Neurotoxicitymentioning

confidence: 99%

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Early and Late Pathomechanisms in Alzheimer’s Disease: From Zinc to Amyloid-β Neurotoxicity

et al. 2016

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There are several systemic and intracerebral pathologic conditions, which limit provision and utilization of energy precursor metabolites in neuronal cells. Energy deficits cause excessive depolarization of neuronal cells triggering glutamate-zinc evoked excitotoxic cascade. The intracellular zinc excess hits several intraneuronal targets yielding collapse of energy balance and impairment functional and structural impairments cholinergic neurons. Disturbances in metabolism of acetyl-CoA, which is a direct precursor for energy, acetylcholine, N-acetyl-l-aspartate and acetylated proteins synthesis, play an important role in these pathomechanisms. Disruption of brain homeostasis activates slow accumulation of amyloid-β1−42, which extra and intracellular oligomeric deposits disrupt diverse transporting and signaling processes in all membrane structures of the cell. Both neurotoxic signals may combine aggravating detrimental effects on neuronal cell. Different neuroglial and neuronal cell types may display differential susceptibility to similar pathogenic insults depending on specific features of their energy and functional parameters. This review, basing on findings gained from cellular and animal models of Alzheimer’s disease, discusses putative energy/acetyl-CoA dependent mechanism in early and late stages of neurodegeneration.

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Section: Acetyl-coa and Amyloid β Neurotoxicitymentioning

confidence: 99%

Section: Acetyl-coa and Amyloid β Neurotoxicitymentioning

confidence: 99%

Early and Late Pathomechanisms in Alzheimer’s Disease: From Zinc to Amyloid-β Neurotoxicity

et al. 2016

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“…Moreover, calcium regulates neural processes such as synaptic plasticity and apoptosis. A change in intracellular calcium levels is involved in the pathogenesis of AD [4546]. In particular, increased intracellular calcium is related to cognitive impairment through neuronal degeneration such as Aβ accumulation and synaptic loss [47].…”

Section: Discussionmentioning

confidence: 99%

Dehydroevodiamine·HCl enhances cognitive function in memory-impaired rat models

Shin

Kim

Suh

2017

Korean J Physiol Pharmacol

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Progressive memory impairment such as that associated with depression, stroke, and Alzheimer's disease (AD) can interfere with daily life. In particular, AD, which is a progressive neurodegenerative disorder, prominently features a memory and learning impairment that is related to changes in acetylcholine and abnormal β-amyloid (Aβ) deposition in the brain. In the present study, we investigated the effects of dehydroevodiamine·HCl (DHED) on cognitive improvement and the related mechanism in memory-impaired rat models, namely, a scopolamine-induced amnesia model and a Aβ1-42-infused model. The cognitive effects of DHED were measured using a water maze test and a passive avoidance test in the memory-impaired rat models. The results demonstrate that DHED (10 mg/kg, p.o.) and Donepezil (1 mg/kg, p.o.) ameliorated the spatial memory impairment in the scopolamine-induced amnestic rats. Moreover, DHED significantly improved learning and memory in the Aβ1-42-infused rat model. Furthermore, the mechanism of these behavioral effects of DHED was investigated using a cell viability assay, reactive oxygen species (ROS) measurement, and intracellular calcium measurement in primary cortical neurons. DHED reduced neurotoxicity and the production of Aβ-induced ROS in primary cortical neurons. In addition, similar to the effect of MK801, DHED decreased intracellular calcium levels in primary cortical neurons. Our results suggest that DHED has strong protective effects against cognitive impairments through its antioxidant activity and inhibition of neurotoxicity and intracellular calcium. Thus, DHED may be an important therapeutic agent for memory-impaired symptoms.

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“…No effect was found also on amyloid beta load in these structures after 3 week of AP-12 administration, indicating that the cholinergic system and amyloid load do not play a crucial role in AP-12 stimulatory effects on learning/memory. At the same time, it is worthwhile to stress the calcium channel blocking properties of AP-12, because it is known that dysregulated Ca 2+ homeostasis in AD patients may affect signaling processes and related pathways [3, 6]. Taking together, the memory enhancing and anxiolytic activities and the influence on brain protein expression obtained in the present study on Tg female mice and did not show a considerable sex specificity if compare with the previously found results in Tg male mice [11].…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenesis of AD is still not clearly understood, but likely, there are multiple mechanisms, such as the extracellular deposition of β-amyloid (Aβ), intraneuronal tau pathology, synaptic loss, impaired neural transmission, Aβ angiopathy and inflammatory processes, together impairing neurons in the hippocampus and cerebral cortex [1]. In addition, there is evidence that altered neuronal Ca 2+ homeostasis can also facilitate neurodegeneration in AD [2–6], therefore attention has been turned to the calcium channel blocking drugs of the 1,4-dihydropyridine (DHPs) series as neuroprotectors in both Parkinson’s disease [7, 8] and AD [9]. …”

Section: Introductionmentioning

confidence: 99%

Memory-enhancing and brain protein expression-stimulating effects of novel calcium antagonist in Alzheimer’s disease transgenic female mice

Jansone

Kadish

Groen

et al. 2016

Pharmacological Research

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The prevalence of Alzheimer’s disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD.

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Ca2+ dysregulation in the endoplasmic reticulum related to Alzheimer’s disease: A review on experimental progress and computational modeling

Cited by 26 publications

References 187 publications

Early and Late Pathomechanisms in Alzheimer’s Disease: From Zinc to Amyloid-β Neurotoxicity

Early and Late Pathomechanisms in Alzheimer’s Disease: From Zinc to Amyloid-β Neurotoxicity

Dehydroevodiamine·HCl enhances cognitive function in memory-impaired rat models

Memory-enhancing and brain protein expression-stimulating effects of novel calcium antagonist in Alzheimer’s disease transgenic female mice

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