Microglial Store-operated Calcium Signaling in Health and in Alzheimer’s Disease

McLarnon, James G.

doi:10.2174/1567205018666210119143817

Cited by 8 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ca 2+ depletion from the ER in turn activates ER STIM1 proteins to translocate proximally to puncta where closely apposed plasma membrane (PM) Orai1 channels are activated. This mechanism underlies store-operated Ca 2+ entry (SOCE) in many cell types ( Prakriya and Lewis, 2015 ), including microglia ( McLarnon, 2020 ; Mizuma et al, 2019 ; Gilbert et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia

Jairaman

McQuade

Granzotto

et al. 2022

eLife

View full text Add to dashboard Cite

The membrane protein TREM2 (Triggering Receptor Expressed on Myeloid cells 2) regulates key microglial functions including phagocytosis and chemotaxis. Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD). Because abnormalities in Ca2+ signaling have been observed in several AD models, we investigated TREM2 regulation of Ca2+ signaling in human induced pluripotent stem cell-derived microglia (iPSC-microglia) with genetic deletion of TREM2. We found that iPSC-microglia lacking TREM2 (TREM2 KO) show exaggerated Ca2+ signals in response to purinergic agonists, such as ADP, that shape microglial injury responses. This ADP hypersensitivity, driven by increased expression of P2Y12 and P2Y13 receptors, results in greater release of Ca2+ from the endoplasmic reticulum (ER) stores, which triggers sustained Ca2+ influx through Orai channels and alters cell motility in TREM2 KO microglia. Using iPSC-microglia expressing the genetically encoded Ca2+ probe, Salsa6f, we found that cytosolic Ca2+ tunes motility to a greater extent in TREM2 KO microglia. Despite showing greater overall displacement, TREM2 KO microglia exhibit reduced directional chemotaxis along ADP gradients. Accordingly, the chemotactic defect in TREM2 KO microglia was rescued by reducing cytosolic Ca2+ using a P2Y12 receptor antagonist. Our results show that loss of TREM2 confers a defect in microglial Ca2+ response to purinergic signals, suggesting a window of Ca2+ signaling for optimal microglial motility.

show abstract

Section: Introductionmentioning

confidence: 99%

TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia

Jairaman

McQuade

Granzotto

et al. 2022

eLife

View full text Add to dashboard Cite

show abstract

“…The migration of monocytes into the AD brain begins with Aβ deposition and contributes to neuronal cell death that causes brain atrophy 66 . Microglial chemotaxis is related to the concentration of soluble Aβ, 67 and migration of microglia induced by Aβ constitutes a chemotactic response of neuroimmune brain cells 68 . Gliogenesis in the adult brain regulates brain function and is involved in neurological conditions such as AD 69,70 …”

Section: Discussionmentioning

confidence: 99%

“…66 Microglial chemotaxis is related to the concentration of soluble Aβ, 67 and migration of microglia induced by Aβ constitutes a chemotactic response of neuroimmune brain cells. 68 Gliogenesis in the adult brain regulates brain function and is involved in neurological conditions such as AD. 69,70 Therefore, genes in the purple module are likely linked to biological processes relevant to AD.…”

Section: F I G U R Ementioning

confidence: 99%

Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease

Kim

Vasanthakumar

et al. 2022

Alz & Dem Diag Ass & Dis Mo

View full text Add to dashboard Cite

Introduction The acceleration of biological aging is a risk factor for Alzheimer's disease (AD). Here, we performed weighted gene co‐expression network analysis (WGCNA) to identify modules and dysregulated genesinvolved in biological aging in AD. Methods We performed WGCNA to identify modules associated with biological clocks and hub genes of the module with the highest module significance. In addition, we performed differential expression analysis and association analysis with AD biomarkers. Results WGCNA identified five modules associated with biological clocks, with the module designated as “purple” showing the strongest association. Functional enrichment analysis revealed that the purple module was related to cell migration and death. Ten genes were identified as hub genes in purple modules, of which CX3CR1 was downregulated in AD and low levels of CX3CR1 expression were associated with AD biomarkers. Conclusion Network analysis identified genes associated with biological clocks, which suggests the genetic architecture underlying biological aging in AD. Highlights Examine links between Alzheimer's disease (AD) peripheral transcriptome and biological aging changes. Weighted gene co‐expression network analysis (WGCNA) found five modules related to biological aging. Among the hub genes of the module, CX3CR1 was downregulated in AD. The CX3CR1 expression level was associated with cognitive performance and brain atrophy.

show abstract

“…In addition, changes in properties of store-operated Ca 2+ entry in microglia could lead to altered immune cell response and neurovascular unit dysfunction in the inflamed AD brain [ 143 ]. The membrane protein TREM2 regulates key microglial functions including phagocytosis and chemotaxis.…”

Section: The Role Of Ca 2+ Homeostasis Dysfunction...mentioning

confidence: 99%

Role of Microglia and Astrocytes in Alzheimer’s Disease: From Neuroinflammation to Ca2+ Homeostasis Dysregulation

Benedetto

Burgaletto

Bellanca

et al. 2022

Cells

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common form of dementia worldwide, with a complex, poorly understood pathogenesis. Cerebral atrophy, amyloid-β (Aβ) plaques, and neurofibrillary tangles represent the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as a prominent feature of the AD brain and substantial evidence suggests that the inflammatory response modulates disease progression. Additionally, dysregulation of calcium (Ca2+) homeostasis represents another early factor involved in the AD pathogenesis, as intracellular Ca2+ concentration is essential to ensure proper cellular and neuronal functions. Although growing evidence supports the involvement of Ca2+ in the mechanisms of neurodegeneration-related inflammatory processes, scant data are available on its contribution in microglia and astrocytes functioning, both in health and throughout the AD continuum. Nevertheless, AD-related aberrant Ca2+ signalling in astrocytes and microglia is crucially involved in the mechanisms underpinning neuroinflammatory processes that, in turn, impact neuronal Ca2+ homeostasis and brain function. In this light, we attempted to provide an overview of the current understanding of the interactions between the glia cells-mediated inflammatory responses and the molecular mechanisms involved in Ca2+ homeostasis dysregulation in AD.

show abstract

Microglial Store-operated Calcium Signaling in Health and in Alzheimer’s Disease

Cited by 8 publications

References 0 publications

TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia

TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia

Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease

Role of Microglia and Astrocytes in Alzheimer’s Disease: From Neuroinflammation to Ca2+ Homeostasis Dysregulation

Contact Info

Product

Resources

About