Calcium ion influx in microglial cells: Physiological and therapeutic significance

Sharma, Purnima; Liao, Ping

doi:10.1002/jnr.23344

Cited by 33 publications

(28 citation statements)

References 130 publications

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“…limited to neurons and myocytes), with [Ca 2+ ] in nonexcitable cells being controlled by other mechanisms such as store-operated Ca 2+ -entry. However, there is increasing evidence that VGCCs are in fact expressed and functional in many non-excitable cells [69], including in some lymphocytes [70,71] and in glia [72][73][74]. It therefore cannot be excluded that VGCCs have a role in [Ca 2+ ] regulation in many cell types, although this would seem likely to be at most a minor contribution to the results reported here, especially since VGCCs are not expressed in platelets or their megakaryocyte precursors [75].…”

Section: Discussionmentioning

confidence: 71%

Cellular calcium in bipolar disorder: systematic review and meta-analysis

et al. 2019

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Calcium signalling has long been implicated in bipolar disorder, especially by reports of altered intracellular calcium ion concentrations ([Ca 2+ ]). However, the evidence has not been appraised critically. We carried out a systematic review and metaanalysis of studies of cellular calcium indices in bipolar disorder. 2281 records were identified and 117 screened, of which 32 were eligible and 21 were suitable for meta-analyses. The latter each involved up to 642 patients and 404 control subjects. We found that basal free intracellular [Ca 2+ ] is increased in bipolar disorder, both in platelets and in lymphocytes. The effect size is 0.55, with an estimated elevation of 29%. It is observed in medication-free patients. It is present in mania and bipolar depression, but data are equivocal for euthymia. Cells from bipolar disorder individuals also show an enhanced [Ca 2+ ] response to stimulation with 5-HT or thrombin, by an estimated 25%, with an effect size of 0.63. In studies which included other diagnoses, intracellular basal [Ca 2+ ] was higher in bipolar disorder than in unipolar depression, but not significantly different from schizophrenia. Functional parameters of cellular Ca 2+ (e.g. calcium transients), and neuronal [Ca 2+ ], have been much less investigated, and no firm conclusions can be drawn. In summary, there is a robust, medium effect size elevation of basal and stimulated free intracellular [Ca 2+ ] in bipolar disorder. The results suggest altered calcium functioning in the disorder, and encourage further investigations into the underlying mechanisms, and the implications for pathophysiology and therapeutics.

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Section: Discussionmentioning

confidence: 71%

Cellular calcium in bipolar disorder: systematic review and meta-analysis

et al. 2019

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“…Homeostatic microglia are considered to be in a sensing state 15 , equipped to detect environmental changes in order to respond to a variety of stimuli. At the center of this transformation is identification of several surface channels and receptors that are critical for entry of calcium ions 16,17 . Thus, PWK are predicted to be a novel strain in which to understand differences related to this process.…”

Section: Resultsmentioning

confidence: 99%

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

Yang

Onos

Choi

et al. 2020

Preprint

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Microglia are now considered drivers of Alzheimer's disease (AD) pathology. However, single-cell RNA-sequencing (scRNA-seq) of microglia in mice, a key preclinical model organsim, have shown mixed results regarding translatability to human studies. To address this, scRNA-seq of microglia from C57BL/6J (B6) and wild-derived strains WSB/EiJ, CAST/EiJ and PWK/PhJ carrying APP/PS1 was performed and demonstrated that genetic diversity significantly altered features and dynamics of microglia in baseline neuroimmune functions and in response to amyloidosis. There was significant variation in abundance of microglial subpopulations, including numbers of disease-associated microglia and interferon-responding microglia across the strains.Further, for each subpopulation, significant gene expression differences were observed between strains, and relative to B6 that included nineteen genes previously associated with human AD including Apoe, Trem2, Bin1 and Sorl1. This resource will be critical in the development of appropriately targeted therapeutics for AD and a range of other neurological diseases. 30 Introduction 31Alzheimer's disease (AD) is defined by the neuropathological accumulation of beta 32 amyloid plaques, neurofibrillary tangles of tau and widespread neuronal loss. AD is the 33 most common cause of adult dementia and is characterized by a wide range of 34 cognitive and behavioral deficits that severely impact quality of life and the ability to self-35 care. Recent work has re-focused the field towards the contribution of brain glial cells to 36 the initiation and spread of these disease-specific pathologies, and specifically on the 37 role of microglia as potentially a causative cell type in driving disease development and 38 progression. Human genome-wide association studies (GWAS) have identified more 39 than 25 variants near genes uniquely expressed in microglia that are predicted to 40 increase susceptibility for AD. In light of this complexity, the mouse represents a critical 41 model system to dissect the role of microglia and other glia in AD. 42 43There has been large debate regarding the alignment of mouse microglia to human 44 microglia in terms of identity, diversity and function. With the more widespread use of 45 single-cell sequencing technology, a number of groups have suggested that the species 46 difference is too great for conclusions drawn from mouse models to inform our 47 understanding of human microglia1,2. Central to this argument is the discovery and 48 description of a specific class of microglia in the mouse, disease-associated microglia 49 (DAM)3. Based upon the current data it is unclear whether the presence or absence of 50 DAM in human AD patients is the result of differences in tissue collection, extraction of 51 cells, genetic diversity of patients, sub-type of AD presented in donors or even the 52 relevant disease1,4. Recent work has demonstrated that single-nucleus RNA 53 sequencing of stored human tissue fails to detect differences in microglia activation 54 between AD and contro...

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“…PLCγ2 hydrolyzes the membrane phospholipid PIP 2 to form the secondary messenger inositol triphosphate (IP 3 ), which promotes the release of calcium into the cytoplasm. Functional alterations of PLCγ2 impact the IP 3 /Ca 2+ signaling pathway, found determinant for microglial properties [68] . Of interest, Tau misfolding could also impact IP 3 production, as it was shown that physiological Tau exerts a tonic inhibition on the phosphatase PTEN reducing the formation of PIP2 [14] .…”

Section: Ad Tauopathies and Inflammation: Genetic Evidencesmentioning

confidence: 99%

Tau and neuroinflammation: What impact for Alzheimer's Disease and Tauopathies?

2018

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Alzheimer's Disease (AD) is a chronic neurodegenerative disorder and the most common type of dementia (60–80% of cases). In 2016, nearly 44 million people were affected by AD or related dementia. AD is characterized by progressive neuronal damages leading to subtle and latter obvious decline in cognitive functions including symptoms such as memory loss or confusion, which ultimately require full-time medical care. Its neuropathology is defined by the extracellular accumulation of amyloid-β (Aβ) peptide into amyloid plaques, and intraneuronal neurofibrillary tangles (NFT) consisting of aggregated hyper- and abnormal phosphorylation of tau protein. The latter, identified also as Tau pathology, is observed in a broad spectrum of neurological diseases commonly referred to as “Tauopathies”. Besides these lesions, sustained neuroinflammatory processes occur, involving notably micro- and astro-glial activation, which contribute to disease progression. Recent findings from genome wide association studies further support an instrumental role of neuroinflammation. While the interconnections existing between this innate immune response and the amyloid pathogenesis are widely characterized and described as complex, elaborated and evolving, only few studies focused on Tau pathology. An adaptive immune response takes place conjointly during the disease course, as indicated by the presence of vascular and parenchymal T-cell in AD patients' brain. The underlying mechanisms of this infiltration and its consequences with regards to Tau pathology remain understudied so far. In the present review, we highlight the interplays existing between Tau pathology and the innate/adaptive immune responses.

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Calcium ion influx in microglial cells: Physiological and therapeutic significance

Cited by 33 publications

References 130 publications

Cellular calcium in bipolar disorder: systematic review and meta-analysis

Cellular calcium in bipolar disorder: systematic review and meta-analysis

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

Tau and neuroinflammation: What impact for Alzheimer's Disease and Tauopathies?

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