Calcium Hypothesis Research Articles

Transcriptome and Animal Model Integration Reveals Inhibition of Calcium Homeostasis-Associated Gene ITPKB Alleviates Amyloid Plaque Deposition.

Alzheimer's disease (AD) is a severe neurological illness that causes memory loss and is a global problem. The calcium hypothesis recently steadily evolved in AD. The prospective targets for calcium homeostasis therapy, however, are limited, and gene expression-level research connected to calcium homeostasis in AD remains hazy. In this study, we analyzed the microarray dataset (GSE132903) taken from the Gene Expression Omnibus (GEO) database to investigate calcium homeostasis-related genes for AD. Using immunoblot analysis, we examined the association of ITPKB with inflammation in AD. Additionally, the immunofluorescence technique was employed to assess the impact of pharmacological inhibition of ITPKB on the amyloid-β (Aβ) plaque deposition in APP/PS1 mice. This article's further exploration of calcium homeostasis-related genes has propelled the validation of the calcium homeostasis theory in AD.

Age- and sex-dependent alterations in primary somatosensory cortex neuronal calcium network dynamics during locomotion.

Over the past 30 years, the calcium (Ca2+ ) hypothesis of brain aging has provided clear evidence that hippocampal neuronal Ca2+ dysregulation is a key biomarker of aging. Age-dependent Ca2+ -mediated changes in intrinsic excitability, synaptic plasticity, and activity have helped identify some of the mechanisms engaged in memory and cognitive decline based on work done mostly at the single-cell level and in the slice preparation. Recently, our lab identified age- and Ca2+ -related neuronal network dysregulation in the cortex of the anesthetized animal. Still, investigations in the awake animal are needed to test the generalizability of the Ca2+ hypothesis of brain aging. Here, we used in vigilo two-photon imaging in ambulating mice, to image GCaMP8f in the primary somatosensory cortex (S1), during ambulation and at rest. We investigated aging- and sex-related changes in neuronal networks in the C56BL/6J mouse. Following imaging, gait behavior was characterized to test for changes in locomotor stability. During ambulation, in both young adult and aged mice, an increase in network connectivity and synchronicity was noted. An age-dependent increase in synchronicity was seen in ambulating aged males only. Additionally, females displayed increases in the number of active neurons, Ca2+ transients, and neuronal activity compared to males, particularly during ambulation. These results suggest S1 Ca2+ dynamics and network synchronicity are likely contributors of locomotor stability. We believe this work raises awareness of age- and sex-dependent alterations in S1 neuronal networks, perhaps underlying the increase in falls with age.

Cigarette smoke triggers calcium overload in mouse hippocampal neurons via the ΔFOSB-CACNA2D1 axis to impair cognitive performance

A growing body of evidence shows that cigarette smoking impairs cognitive performance. The 'Calcium Hypothesis' theory of neuronopathies reveals a critical role of aberrant calcium signaling in compromised cognitive functions. However, the underlying implications of abnormalities in calcium signaling in the neurotoxicity induced by cigarette smoke (CS) have not yet been identified. CACNA2D1, an important auxiliary subunit involved in the composition of voltage-gated calcium channels (VGCCs), was reported to affect the calcium signaling in neurons by facilitating VGCCs-mediated Ca2+ influx. ΔFOSB, an alternatively-spliced product of the Fosb gene, is an activity-dependent transcription factor induced robustly in the brain in response to environmental stimuli such as CS. Interestingly, our preliminary bioinformatics analysis revealed a significant co-expression between ΔFOSB and CACNA2D1 in brain tissues of patients with neurodegenerative diseases characterized by progressive cognitive decline. Therefore, we hypothesized that the activation of the ΔFOSB-CACNA2D1 axis in response to CS exposure might cause dysregulation of calcium homeostasis in hippocampal neurons via VGCCs-mediated Ca2+ influx, thereby contributing to cognitive deficits. To this end, the present study established a CS-induced mouse model of hippocampus-dependent cognitive impairment, in which the activation of the ΔFOSB-CACNA2D1 axis accompanied by severe calcium overload was observed in the mouse hippocampal tissues. More importantly, ΔFOSB knockdown-/overexpression-mediated inactivation/activation of the ΔFOSB-CACNA2D1 axis interdicted/mimicked CS-induced dysregulation of calcium homeostasis followed by severe cellular damage in HT22 mouse hippocampal neurons. Mechanistically speaking, a further ChIP-qPCR assay confirmed the physical interaction between transcription factor ΔFOSB and the Cacna2d1 gene promoter, suggesting a direct transcriptional regulation of the Cacna2d1 gene by ΔFOSB. Overall, our current work aims to deliver a unique insight into the neurotoxic mechanisms induced by CS to explore potential targets for intervention.

Calcium sensor Yellow Cameleon 3.6 as a tool to support the calcium hypothesis of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with increasing relevance as dementia cases rise. The etiology of AD is widely debated. The Calcium Hypothesis of Alzheimer's disease and brain aging states that the dysfunction of calcium signaling is the final common pathway leading to neurodegeneration. When the Calcium Hypothesis was originally coined, the technology did not exist to test it, but with the advent of Yellow Cameleon 3.6 (YC3.6) we are able to test its validity. Here we review use of YC3.6 in studying Alzheimer's disease using mouse models and discuss whether these studies support or refute the Calcium Hypothesis. YC3.6 studies showed that amyloidosis preceded dysfunction in neuronal calcium signaling and changes in synapse structure. This evidence supports the Calcium Hypothesis. In vivo YC3.6 studies point to calcium signaling as a promising therapeutic target; however, additional work is necessary to translate these findings to humans.

Deep Learning to Detect the Function of Calmodulin in Alzheimer’s Disease

Alzheimer’s disease (AD) is marked by losses in cognitive functions. Hallmarks of AD, amyloid beta (Aβ) plaques and neurofibrillary tangles, are intercellular structures that are highly associated with AD. The accumulations of these molecules could be seen as results of other events in prior stages of AD. The calcium hypothesis was first proposed to explain the forming of these hallmarks while the calmodulin (CaM) hypothesis was proposed to provide more improved insight later. The CaM hypothesis states that the uncontrolled flux of calcium ions in the neurons is the cause of neurodegeneration. In addition, the critical role of CaM and CaM-binding proteins (CaMBPs) are identified in the hypothesis. In this project, the regulating role of CaM and CaM-related protein in AD are discussed, including CaMBPs, critical receptors and risk factors. Besides, the potential therapeutic target related to CaM are also mentioned to provide a promise direction of treatment for AD.

Mitochondrial Ca2+ Signaling and Bioenergetics in Alzheimer's Disease.

Alzheimer's disease (AD) is a hereditary and sporadic neurodegenerative illness defined by the gradual and cumulative loss of neurons in specific brain areas. The processes that cause AD are still under investigation and there are no available therapies to halt it. Current progress puts at the forefront the "calcium (Ca2+) hypothesis" as a key AD pathogenic pathway, impacting neuronal, astrocyte and microglial function. In this review, we focused on mitochondrial Ca2+ alterations in AD, their causes and bioenergetic consequences in neuronal and glial cells, summarizing the possible mechanisms linking detrimental mitochondrial Ca2+ signals to neuronal death in different experimental AD models.

Calcium Signaling Regulated by Cellular Membrane Systems and Calcium Homeostasis Perturbed in Alzheimer's Disease.

Although anything that changes spatiotemporally could be a signal, cells, particularly neurons, precisely manipulate calcium ion (Ca2+) to transmit information. Ca2+ homeostasis is indispensable for neuronal functions and survival. The cytosolic Ca2+ concentration ([Ca2+]CYT) is regulated by channels, pumps, and exchangers on cellular membrane systems. Under physiological conditions, both endoplasmic reticulum (ER) and mitochondria function as intracellular Ca2+ buffers. Furthermore, efficient and effective Ca2+ flux is observed at the ER-mitochondria membrane contact site (ERMCS), an intracellular membrane juxtaposition, where Ca2+ is released from the ER followed by mitochondrial Ca2+ uptake in sequence. Hence, the ER intraluminal Ca2+ concentration ([Ca2+]ER), the mitochondrial matrix Ca2+ concentration ([Ca2+]MT), and the [Ca2+]CYT are related to each other. Ca2+ signaling dysregulation and Ca2+ dyshomeostasis are associated with Alzheimer’s disease (AD), an irreversible neurodegenerative disease. The present review summarizes the cellular and molecular mechanism underlying Ca2+ signaling regulation and Ca2+ homeostasis maintenance at ER and mitochondria levels, focusing on AD. Integrating the amyloid hypothesis and the calcium hypothesis of AD may further our understanding of pathogenesis in neurodegeneration, provide therapeutic targets for chronic neurodegenerative disease in the central nervous system.

Low Intensity Electromagnetic Fields Act via Voltage-Gated Calcium Channel (VGCC) Activation to Cause Very Early Onset Alzheimer's Disease: 18 Distinct Types of Evidence.

Electronically generated electromagnetic fields (EMFs), including those used in wireless communication such as cell phones, Wi-Fi and smart meters, are coherent, producing very high electric and magnetic forces, which act on the voltage sensor of voltage-gated calcium channels to produce increases in intracellular calcium [Ca2+]i. The calcium hypothesis of Alzheimer’s disease (AD) has shown that each of the important AD-specific and nonspecific causal elements is produced by excessive [Ca2+]i. [Ca2+]i acts in AD via excessive calcium signaling and the peroxynitrite/oxidative stress/inflammation pathway, which are each elevated by EMFs.An apparent vicious cycle in AD involves amyloid-beta protein (Aβ) and [Ca2+]i. Three types of epidemiology suggest EMF causation of AD, including early onset AD. Extensive animal model studies show that low intensity EMFs cause neurodegeneration, including AD, with AD animals having elevated levels of Aβ, amyloid precursor protein and BACE1. Rats exposed to pulsed EMFs every day are reported to develop universal or near universal very early onset neurodegeneration, including AD; these findings are superficially similar to humans with digital dementia. EMFs producing modest increases in [Ca2+]i can also produce protective, therapeutic effects. The therapeutic pathway and peroxynitrite pathway inhibit each other. A summary of 18 different findings is provided, which collectively provide powerful evidence for EMF causation of AD. The author is concerned that smarter, more highly pulsed “smart” wireless communication may cause widespread very, very early onset AD in human populations.

Calcium Dyshomeostasis in Alzheimer's Disease Pathogenesis.

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that is characterized by amyloid β-protein deposition in senile plaques, neurofibrillary tangles consisting of abnormally phosphorylated tau protein, and neuronal loss leading to cognitive decline and dementia. Despite extensive research, the exact mechanisms underlying AD remain unknown and effective treatment is not available. Many hypotheses have been proposed to explain AD pathophysiology; however, there is general consensus that the abnormal aggregation of the amyloid β peptide (Aβ) is the initial event triggering a pathogenic cascade of degenerating events in cholinergic neurons. The dysregulation of calcium homeostasis has been studied considerably to clarify the mechanisms of neurodegeneration induced by Aβ. Intracellular calcium acts as a second messenger and plays a key role in the regulation of neuronal functions, such as neural growth and differentiation, action potential, and synaptic plasticity. The calcium hypothesis of AD posits that activation of the amyloidogenic pathway affects neuronal Ca2+ homeostasis and the mechanisms responsible for learning and memory. Aβ can disrupt Ca2+ signaling through several mechanisms, by increasing the influx of Ca2+ from the extracellular space and by activating its release from intracellular stores. Here, we review the different molecular mechanisms and receptors involved in calcium dysregulation in AD and possible therapeutic strategies for improving the treatment.

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

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.

RyR2 calcium channels in the spotlight—I’m ready for my close up, Dr. Alzheimer!

While various hypotheses surrounding the etiology of Alzheimer’s disease (AD) have waxed and waned over the years, the calcium hypothesis of aging [1] has maintained its steady trajectory since the early 1990′s, albeit often as the understudy. Here, Yao et al., [2] further implicate intracellular calcium dysregulation in AD pathogenesis, and focus the spotlight on the elusive ryanodine receptor-2 isoform.

Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium

SUMMARYSynaptic activity-induced calcium (Ca2+) influx and subsequent propagation into the nucleus is a major way in which synapses communicate with the nucleus to regulate transcriptional programs important for activity-dependent survival and memory formation. Nuclear Ca2+ shapes the transcriptome by regulating cyclic AMP (cAMP) response element-binding protein (CREB). Here, we utilize a Drosophila model of tauopathy and induced pluripotent stem cell (iPSC)-derived neurons from humans with Alzheimer’s disease to study the effects of pathogenic tau, a pathological hallmark of Alzheimer’s disease and related tauopathies, on nuclear Ca2+. We find that pathogenic tau depletes nuclear Ca2+ and CREB to drive neuronal death, that CREB-regulated genes are over-represented among differentially expressed genes in tau transgenic Drosophila, and that activation of big potassium (BK) channels elevates nuclear Ca2+ and suppresses tau-induced neurotoxicity. Our studies identify nuclear Ca2+ depletion as a mechanism contributing to tau-induced neurotoxicity, adding an important dimension to the calcium hypothesis of Alzheimer’s disease.

The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

Ca2+ is a ubiquitous second messenger that plays an essential role in physiological processes such as muscle contraction, neuronal secretion, and cell proliferation or differentiation. There is ample evidence that the dysregulation of Ca2+ signaling is one of the key events in the development of neurodegenerative processes, an idea called the “calcium hypothesis” of neurodegeneration. Caenorhabditis elegans (C. elegans) is a very good model for the study of aging and neurodegeneration. In fact, many of the signaling pathways involved in longevity were first discovered in this nematode, and many models of neurodegenerative diseases have also been developed therein, either through mutations in the worm genome or by expressing human proteins involved in neurodegeneration (β-amyloid, α-synuclein, polyglutamine, or others) in defined worm tissues. The worm is completely transparent throughout its whole life, which makes it possible to carry out Ca2+ dynamics studies in vivo at any time, by expressing Ca2+ fluorescent probes in defined worm tissues, and even in specific organelles such as mitochondria. This review will summarize the evidence obtained using this model organism to understand the role of Ca2+ signaling in aging and neurodegeneration.

Calcium Hypothesis of Gulf War Illness: Role of Calcium Ions in Neurological Morbidities in a DFP-Based Rat Model for Gulf War Illness.

Gulf War Illness (GWI) refers to a multi-system disorder that afflicts approximately 30% of First Gulf War (GW) veterans. Amongst the symptoms exhibited, mood and memory impairment are commonly reported by GW veterans. Exposure to organophosphate (OP) compounds which target the cholinergic system is considered a leading cause for GWI symptoms. It is hypothesized that chronic OP-based war-time stimulation of cholinergic signaling led to recruitment of excitatory glutamatergic signaling and other downstream signaling cascades leading to neuronal injury, neuroinflammation, generation of reactive oxygen species, oxidative stress, and mitochondrial damage within the central nervous system. These findings have been observed in both experimental models and GWI veterans. In this context the role of calcium (Ca2+) signaling in GWI has come to the forefront. Here we present our Ca2+ hypothesis of GWI that suggests sustained neuronal Ca2+ elevations serve as a molecular trigger for pathological synaptic plasticity that has allowed for the persistence of GWI symptoms. Subsequently we discuss that therapeutic targeting of Ca2+ homeostatic mechanisms provides novel targets for effective treatment of GWI-related neurological signs in our rodent model.

Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium Mediated by BK Channels

Synaptic activity-induced calcium ion (Ca2+) influx and subsequent propagation of Ca2+ into the nucleus is a major way in which synapses communicate with the nucleus to regulate transcriptional programs that maintain activity-dependent survival and mediate memory formation. Nuclear Ca2+ shapes the transcriptome by regulating cAMP response element-binding protein (CREB)-dependent transcription. Here we utilize Drosophila and induced pluripotent stem cell (iPSC)-derived neurons from humans with Alzheimer’s disease to study the effects of pathogenic tau, a hallmark of Alzheimer’s disease and related “tauopathies,” on nuclear Ca2+. We find that pathogenic tau depletes nuclear Ca2+ and CREB to drive neuronal death. Mechanistically, we find that big potassium (BK) channels regulate depletion of nuclear Ca2+ in tauopathy, and that genetic and pharmacologic manipulation of nuclear Ca2+ and BK channels modifies tau neurotoxicity. Our studies identify the BK channel/nuclear Ca2+/CREB axis as a previously unknown mechanism contributing to tau-induced neurotoxicity, adding a new dimension to the Calcium Hypothesis of Alzheimer’s Disease.

Alzheimer's Disease: A short introduction to the calmodulin hypothesis.

At the cellular level, Alzheimer's disease (AD) is characterized by the presence of intracellular plaques containing amyloid beta (Aβ) protein and neurofibrillary tangles consisting of phospho-tau (p-tau). These biomarkers are considered to contribute, at least in part, to the neurodegenerative events of the disease. But the accumulation of plaques and tangles is widely considered to be a later event with other factors likely being the cause of the disease. Calcium dysregulation—the unregulated accumulation of calcium ions—in neurons is an early event that underlies neurodegeneration. In 2002, O'Day and Myre extended this “Calcium Hypothesis” to include calmodulin (CaM) the primary target of calcium, suggesting the “Calmodulin Hypothesis” as an updated alternative. Here we overview the central role of CaM in the formation of the classic hallmarks of AD: plaques and tangles. Then some insight into CaM's binding to various risk factor proteins is given followed by a short summary of specific receptors and channels linked to the disease that are CaM binding proteins. Overall, this review emphasizes the diversity of Alzheimer's-linked CaM-binding proteins validating the hypothesis that CaM operates critically at all stages of the disease and stands out as a potential primary target for future research.

Reduced Cytosolic Calcium as an Early Decisive Cellular State in Parkinson's Disease and Synucleinopathies.

The more than 30-year-old Calcium hypothesis postulates that dysregulation in calcium dependent processes in the aging brain contributes to its increased vulnerability and this concept has been extended to Alzheimer’s disease and Parkinson’s disease. Central to the hypothesis is that increased levels of intracellular calcium develop and contributes to neuronal demise. We have studied the impact on cells encountering a gradual build-up of aggregated α-synuclein, which is a central process to Parkinson’s disease and other synucleinopathies. Surprisingly, we observed a yet unrecognized phase characterized by a reduced cytosolic calcium in cellular and neuronal models of Parkinson’s disease, caused by α-synuclein aggregates activating the endoplasmic calcium ATPase, SERCA. Counteracting the initial phase with low calcium rescues the subsequent degenerative phase with increased calcium and cell death – and demonstrates this early phase initiates decisive degenerative signals. In this review, we discuss our findings in relation to literature on calcium dysregulation in Parkinson’s disease and dementia.

Dysregulation of Intracellular Calcium Signaling in Alzheimer's Disease.

Calcium (Ca2+) hypothesis of Alzheimer's disease (AD) gains popularity. It points to new signaling pathways that may underlie AD pathogenesis. Based on calcium hypothesis, novel targets for the development of potential AD therapies are identified. Recent Advances: Recently, the key role of neuronal store-operated calcium entry (nSOCE) in the development of AD has been described. Correct regulation of nSOCE is necessary for the stability of postsynaptic contacts to preserve the memory formation. Molecular identity of hippocampal nSOCE is defined. Perspective nSOCE-activating molecule, prototype of future anti-AD drugs, is described. Endoplasmic reticulum Ca2+ overload happens in many but not in all AD models. The nSOCE targeting therapy described in this review may not be universally applicable. There is a need to determine whether AD is a syndrome with one critical signaling pathway that initiates pathology, or it is a disorder with many different signaling pathways that are disrupted simultaneously or one after each other. It is necessary to validate applicability of nSOCE-activating therapy for the development of anti-AD medication. There is an experimental correlation between downregulated nSOCE and disrupted postsynaptic contacts in AD mouse models. Signaling mechanisms downstream of nSOCE which are responsible for the regulation of stability of postsynaptic contacts have to be discovered. That will bring new targets for the development of AD-preventing therapies. Antioxid. Redox Signal. 29, 1176-1188.

Regulation of bone mineral density in the grey squirrel, Sciurus carolinensis: Bioavailability of calcium oxalate, and implications for bark stripping.

SummaryThe damage caused when grey squirrels strip the outer bark off trees and ingest the underlying phloem can result in reduced timber quality or tree death. This is extremely costly to the UK forestry industry and can alter woodland composition, hampering conservation efforts. The calcium hypothesis proposes that grey squirrels ingest phloem to ameliorate a seasonal calcium deficiency. Calcium in the phloem predominantly takes the form of calcium oxalate (CaOx), however not all mammals can utilise CaOx as a source of calcium. Here, we present the results of a small‐scale study to determine the extent to which grey squirrels can utilise CaOx. One of three custom‐made diets containing calcium in varying forms and quantities (CaOx diet, Low‐calcium carbonate (CaCO 3) diet and Control diet) were fed to three treatment groups of six squirrels for 8 weeks. Bone densitometric properties were measured at the end of this time using peripheral quantitative computed tomography and micro‐computed tomography. Pyridinoline—a serum marker of bone resorption—was measured regularly throughout the study. Bone mineral density and cortical mineralisation were lower in squirrels fed the CaOx diet compared to the Control group but similar to that of those on the Low‐calcium diet, suggesting that calcium from calcium oxalate was not effectively utilised to maintain bone mineralisation. Whilst no differences were observed in serum pyridinoline levels between individuals on different diets, females had on average higher levels than males throughout the study. Future work should seek to determine if this apparent lack of ability to utilise CaOx is common to a large sample of grey squirrels and if so, whether it is consistent across all areas and seasons.

Calcium Hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis

This article updates the Calcium Hypothesis of Alzheimer's disease and brain aging on the basis of emerging evidence since 1994 (The present article, with the subtitle “New evidence for a central role of Ca2+ in neurodegeneration,” includes three appendices that provide context and further explanations for the rationale for the revisions in the updated hypothesis—the three appendices are as follows: Appendix I “Emerging concepts on potential pathogenic roles of [Ca2+],” Appendix II “Future studies to validate the central role of dysregulated [Ca2+] in neurodegeneration,” and Appendix III “Epilogue: towards a comprehensive hypothesis.”) (Marx J. Fresh evidence points to an old suspect: calcium. Science 2007; 318:384–385). The aim is not only to re-evaluate the original key claims of the hypothesis with a critical eye but also to identify gaps in knowledge required to validate relevant claims and delineate additional studies and/or data that are needed. Some of the key challenges for this effort included examination of questions regarding (1) the temporal and spatial relationships of molecular mechanisms that regulate neuronal calcium ion (Ca2+), (2) the role of changes in concentration of calcium ion [Ca2+] in various subcellular compartments of neurons, (3) how alterations in Ca2+ signaling affect the performance of neurons under various conditions, ranging from optimal functioning in a healthy state to conditions of decline and deterioration in performance during aging and in disease, and (4) new ideas about the contributions of aging, genetic, and environmental factors to the causal relationships between dysregulation of [Ca2+] and the functioning of neurons (see Appendices I and II). The updated Calcium Hypothesis also includes revised postulates that are intended to promote further crucial experiments to confirm or reject the various predictions of the hypothesis (see Appendix III).