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Cited by 190Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeuroscience and Neuropharmacology Research

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

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Di Benedetto, Giulia, Burgaletto, Chiara, Bellanca, Carlo Maria, Munafò, Antonio, Bernardini, Renato, Cantarella, Giuseppina·2022·Cells
DOI 10.3390/cells11172728PMC PMC9454513
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Abstract

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.

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Crossref · 10.3390/cells11172728

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Figure 1 Crosstalk between Ca2+ dysregulation and neuroinflammation in Alzheimer’s disease. Among many other possible causes, the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the AD brain, besides inducing microglia activation, bring about Ca2+ dysregulation in astrocytes. Ca2+ dysregulation increase calcineurin (CN) activity in astrocytes with AD, where CN assumes control over gene regulation through the activation of nuclear factor of activated T cells (NFAT) transcription factors, leading to the production and release of several inflammatory mediators, such as cytokines. In turn, inflammatory factors induce Ca2+ dysregulation and activation of the MAP kinase signalling pathways (p38) in neurons, leading to increased CN activity. Hyperactivation of CN in neurons determines transcriptional repression of several genes, especially those related to synapse function and integrity, causing synaptic plasticity deficits, neurite degeneration, and cognitive impairment. These parameters further participate in the activation of nearby astrocytes leading to the dysregulation of astrocytic Ca2+ and hyperactivity of astrocytic CN that, through the regulation of the transcriptional induction of genes, sustain glial activation and neuroinflammation, negatively affecting neurons and exacerbating neuronal Ca2+ dysregulation. Perpetuation of this vicious cycle drives the progression of AD pathology.
Figure 1 Crosstalk between Ca2+ dysregulation and neuroinflammation in Alzheimer’s disease. Among many other possible causes, the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the AD brain, besides inducing microglia activation, bring about Ca2+ dysregulation in astrocytes. Ca2+ dysregulation increase calcineurin (CN) activity in astrocytes with AD, where CN assumes control over gene regulation through the activation of nuclear factor of activated T cells (NFAT) transcription factors, leading to the production and release of several inflammatory mediators, such as cytokines. In turn, inflammatory factors induce Ca2+ dysregulation and activation of the MAP kinase signalling pathways (p38) in neurons, leading to increased CN activity. Hyperactivation of CN in neurons determines transcriptional repression of several genes, especially those related to synapse function and integrity, causing synaptic plasticity deficits, neurite degeneration, and cognitive impairment. These parameters further participate in the activation of nearby astrocytes leading to the dysregulation of astrocytic Ca2+ and hyperactivity of astrocytic CN that, through the regulation of the transcriptional induction of genes, sustain glial activation and neuroinflammation, negatively affecting neurons and exacerbating neuronal Ca2+ dysregulation. Perpetuation of this vicious cycle drives the progression of AD pathology.CC BY · PubMed Central
Figure 2 Schematic representation of Ca2+ homeostasis dysregulation in microglia and astrocytes in AD. P2X7R, purinergic P2X7 receptor; NLRP3, NOD-like receptor pyrin domain containing 3; Calhm1, Ca2+ homeostasis modulator family member 1; TREM2, triggering receptor expressed on myeloid cells 2; pCREB, phosphorylated cAMP response element binding protein; Calhm2, Ca2+ homeostasis modulator family member 2; mGluR5, metabotropic glutamate receptor 5; IP3R1, Inositol 1,4,5-trisphosphate (IP3) receptor type1; L-type VGGCs, L-type voltage-gated Ca2+ channels; RyRs, Ryanodine receptors. Created with BioRender.com; accessed on 29 July 2022.
Figure 2 Schematic representation of Ca2+ homeostasis dysregulation in microglia and astrocytes in AD. P2X7R, purinergic P2X7 receptor; NLRP3, NOD-like receptor pyrin domain containing 3; Calhm1, Ca2+ homeostasis modulator family member 1; TREM2, triggering receptor expressed on myeloid cells 2; pCREB, phosphorylated cAMP response element binding protein; Calhm2, Ca2+ homeostasis modulator family member 2; mGluR5, metabotropic glutamate receptor 5; IP3R1, Inositol 1,4,5-trisphosphate (IP3) receptor type1; L-type VGGCs, L-type voltage-gated Ca2+ channels; RyRs, Ryanodine receptors. Created with BioRender.com; accessed on 29 July 2022.CC BY · PubMed Central

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Metadata

Authors
Di Benedetto, G., Burgaletto, C., Bellanca, C. M., Munafò, A., Bernardini, R., & Cantarella, G.
Affiliations
  • Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, 95123 Catania, Italy
  • University of Catania (IT)
Corresponding author
Bernardini, Renato
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2022-09-01
Volume
11
Issue
17
Pages
2728
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells11172728
PMC
PMC9454513
OpenAlex
W4294151542
Cited by
189
References
187
Citations by year
2026: 53 · 2025: 63 · 2024: 46 · 2023: 19 · 2022: 8
FWCI
3.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
the Italian Ministry of Research (2017YH3SXK)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Alzheimer's disease, microglia, astrocytes, neuroinflammation, calcium homeostasis, calcium signaling, glial interactions, amyloid plaques, neurofibrillary tangles, neurodegeneration, glial inflammation
MeSH terms
Neuroinflammatory Diseases, Alzheimer Disease, Astrocytes, Homeostasis, Humans, Microglia, Plaque, Amyloid

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