Calcium Signaling During Brain Aging and Its Influence on the Hippocampal Synaptic Plasticity

Kumar, Ashok

doi:10.1007/978-3-030-12457-1_39

Cited by 19 publications

(10 citation statements)

References 269 publications

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“…The 'calcium hypothesis of AD', proposed in 1984 by Khachaturian, suggests a link between Ca 2+ dyshomeostasis, neurodegeneration and AD pathophysiology (Khachaturian, 1984). Since then, numerous studies have investigated the role of Ca 2+ in the pathogenesis of different neurological conditions, including AD, and these are reviewed elsewhere (Agostini and Fasolato, 2016;Galla et al, 2020;Kumar, 2020). The identification of nuclear Ca 2+ signaling as a critical regulator of higher-order brain function points toward the potential involvement of dysregulated nuclear Ca 2+ signaling in the etiology of diseases and mental disorders.…”

Section: Nuclear Ca 2+ -Mediated Neuroprotection and Degenerationmentioning

confidence: 99%

The role of nuclear Ca2+ in maintaining neuronal homeostasis and brain health

Mozolewski

Jeziorek

Schuster

et al. 2021

Journal of Cell Science

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Nuclear Ca2+ has emerged as one of the most potent mediators of the dialogue between neuronal synapses and the nucleus that regulates heterochromatin states, transcription factor activity, nuclear morphology and neuronal gene expression induced by synaptic activity. Recent studies underline the importance of nuclear Ca2+ signaling in long-lasting, activity-induced adaptation and maintenance of proper brain function. Diverse forms of neuroadaptation require transient nuclear Ca2+ signaling and cyclic AMP-responsive element-binding protein (CREB1, referred to here as CREB) as its prime target, which works as a tunable switch to drive and modulate specific gene expression profiles associated with memory, pain, addiction and neuroprotection. Furthermore, a reduction of nuclear Ca2+ levels has been shown to be neurotoxic and a causal factor driving the progression of neurodegenerative disorders, as well as affecting neuronal autophagy. Because of its central role in the brain, deficits in nuclear Ca2+ signaling may underlie a continuous loss of neuroprotection in the aging brain, contributing to the pathophysiology of Alzheimer's disease. In this Review, we discuss the principles of the ‘nuclear calcium hypothesis’ in the context of human brain function and its role in controlling diverse forms of neuroadaptation and neuroprotection. Furthermore, we present the most relevant and promising perspectives for future studies.

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Section: Nuclear Ca 2+ -Mediated Neuroprotection and Degenerationmentioning

confidence: 99%

The role of nuclear Ca2+ in maintaining neuronal homeostasis and brain health

Mozolewski

Jeziorek

Schuster

et al. 2021

Journal of Cell Science

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“…Altered cytosolic Ca 2+ responses have been found in peripheral cells from SAD or FAD patients [122,123]. Lately, dysregulation of Ca 2+ handling has been reported in different AD mouse models (reviewed in [124]), as well as in aged and diseased brains (reviewed in [125]). mRNA levels of several genes involved in the maintenance of Ca 2+ homeostasis have been found to be altered in cerebral tissues from AD patients [126], further sustaining a link between Ca 2+ signaling defects and the pathology.…”

Section: Presenilin 2 and Ca 2+ Homeostasismentioning

confidence: 99%

Intracellular Calcium Dysregulation by the Alzheimer’s Disease-Linked Protein Presenilin 2

Galla

Redolfi

Pozzan

et al. 2020

IJMS

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Alzheimer’s disease (AD) is the most common form of dementia. Even though most AD cases are sporadic, a small percentage is familial due to autosomal dominant mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes. AD mutations contribute to the generation of toxic amyloid β (Aβ) peptides and the formation of cerebral plaques, leading to the formulation of the amyloid cascade hypothesis for AD pathogenesis. Many drugs have been developed to inhibit this pathway but all these approaches currently failed, raising the need to find additional pathogenic mechanisms. Alterations in cellular calcium (Ca2+) signaling have also been reported as causative of neurodegeneration. Interestingly, Aβ peptides, mutated presenilin-1 (PS1), and presenilin-2 (PS2) variously lead to modifications in Ca2+ homeostasis. In this contribution, we focus on PS2, summarizing how AD-linked PS2 mutants alter multiple Ca2+ pathways and the functional consequences of this Ca2+ dysregulation in AD pathogenesis.

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“…Perturbations of intracellular Ca 2+ concentration underlie the increased vulnerability of neurons to age-related processes like cognitive decline and degenerative neurological diseases including, Alzheimer’s and Parkinson’s disease (Disterhoft et al, 1994 ; Kirischuk and Verkhratsky, 1996 ; Lopez et al, 2008 ; Alzheimer’s Association Calcium Hypothesis, 2017 ; Kumar, 2020 ). The age-related cognitive decline includes impairment in retrieving intermediate-term memories, especially episodic memories that rely on spatial and temporal contexts (Tromp et al, 2015 ; Gollan and Goldrick, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Memory and Learning Deficits Are Associated With Ca2+ Dyshomeostasis in Normal Aging

Uryash

Flores

Adams

et al. 2020

Front. Aging Neurosci.

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Neuronal intracellular Ca 2+ homeostasis is critical to the normal physiological functions of neurons and neuronal Ca 2+ dyshomeostasis has been associated with the age-related decline of cognitive functions. Accumulated evidence indicates that the underlying mechanism for this is that abnormal intracellular Ca 2+ levels stimulate the dysregulation of intracellular signaling, which subsequently induces neuronal cell death. We examined intracellular Ca 2+ homeostasis in cortical (in vivo) and hippocampal (in vitro) neurons from young (3-months), middle-age (12-months), and aged (24-months) wild type C57BL6J mice. We found a progressive age-related elevation of intracellular resting calcium ([Ca 2+ ] r) in cortical (in vivo) and hippocampal (in vitro) neurons associated with increased hippocampal neuronal calpain activity and reduced cell viability. In vitro, removal of extracellular Ca 2+ or treatment with SAR7334 or dantrolene reduced [Ca 2+ ] r in all age groups and dantrolene treatment lowered calpain activity and increased cell viability. In vivo, both middle-aged and aged mice showed cognitive deficits compared to young mice, which improved after dantrolene treatment. These findings support the hypothesis that intracellular Ca 2+ dyshomeostasis is a major mechanism underlying the cognitive deficits seen in both normal aging and degenerative neurologic diseases.

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Calcium Signaling During Brain Aging and Its Influence on the Hippocampal Synaptic Plasticity

Cited by 19 publications

References 269 publications

The role of nuclear Ca2+ in maintaining neuronal homeostasis and brain health

The role of nuclear Ca2+ in maintaining neuronal homeostasis and brain health

Intracellular Calcium Dysregulation by the Alzheimer’s Disease-Linked Protein Presenilin 2

Memory and Learning Deficits Are Associated With Ca2+ Dyshomeostasis in Normal Aging

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