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Cited by 99Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Astroglial Calcium Signaling in Aging and Alzheimer's Disease

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Verkhratsky, Alexei·2019·Cold Spring Harbor Perspectives in Biology
DOI 10.1101/cshperspect.a035188PMC PMC6601464
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Abstract

Astrocytes are the homeostatic and protective cells of the central nervous system (CNS).In neurological diseases, astrocytes undergo complex changes, which are subclassified into (1) reactive astrogliosis, an evolutionary conserved defensive rearrangement of cellular phenotype aimed at neuroprotection; (2) pathological remodeling, when astrocytes acquire new features driving pathology; and (3) astrodegeneration, which is manifested by astroglial atrophy and loss of homeostatic functions.In aging brains as well as in the brains affected by Alzheimer's disease (AD), astrocytes acquire both atrophic and reactive phenotypes in a region-and disease-stage-dependent manner.Prevalence of atrophy overreactivity, observed in certain brain regions and in terminal stages of the disease, arguably facilitates the development of neurological deficits.Astrocytes exhibit ionic excitability mediated by changes in intracellular concentration of ions, most importantly of Ca 2+ and Na + , with intracellular ion dynamics triggered by the activity of neural networks.AD astrocytes associated with senile plaques demonstrate Ca 2+ hyperactivity in the form of aberrant Ca 2+ oscillations and pathological long-range Ca 2+ waves.Astroglial Ca 2+ signaling originating from Ca 2+ release from the endoplasmic reticulum is a key factor in initiating astrogliotic response; deficient Ca 2+ signaling toolkits observed in entorhinal and prefrontal cortices of AD model animals may account for vulnerability of these regions to the pathology. THE BRAIN AGINGT he cellular mechanisms of aging in general, and of brain aging in particular, remain controversial; many hypotheses have been proposed, while no unifying theory has been agreed upon.Brain senescence is associated with a progressive loss of function with deficits in learning and memory, and yet, surprisingly, the healthy brain withstands the process of aging remark-ably better than other organs and systems.Indeed, the physical fitness of youth cannot be matched even at middle age, when the cognitive capabilities are reaching their zenith.Indeed, brain cognitive capacity lasts well into advanced age.This bright scenario of extended cognitive capacity, however, is not universal because aging is the chief risk factor for the development of neurodegenerative pathologies that invariably end in senile dementia characterized by severe

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  • Atrophied astrocytes fail to maintain the glutamate‐glutamine shuttle and display insufficient glutamate clearance because of reduced synaptic coverage, contributing to synaptic extinction and cognitive deficiency.

    “previous reports have shown that atrophied astrocytes fail to maintain the glutamate‐glutamine shuttle [28, 47] and display insufficient glutamate clearance [43] because of reduced synaptic coverage [45, 46, 47], contributing to synaptic extinction and cognitive deficiency [43].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [47]

    The ‘Astroglia in Aging’ section links astrocytic atrophy and reduced glutamine synthetase expression to *possible* abnormalities in neurotransmission; it does not establish that atrophied astrocytes fail to maintain the glutamate–glutamine shuttle. The ‘Astrogliopathology in Alzheimer’s Disease’ section reports atrophic astrocytes with altered glutamate-transporter distribution, but does not establish the reduced synaptic coverage attributed to this source. The cited passages provide no page numbers. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Atrophied astrocytes are characterized by decreased cell size and reduction of complexity.

    “Atrophied astrocytes are characterized by decreased cell size and reduction of complexity [45, 46, 47].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [47]

  • GS decreases in aging, AD, and reactive astrocytes.

    “It has been described that GS decreases in aging [47], AD [112], and reactive astrocytes [94].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [47]

    The citation [94] is attached specifically to the claim that GS decreases in reactive astrocytes. The ‘Astroglia in Aging’ section mentions an age-dependent decrease in GS expression, but does not link it to reactive astrocytes; the sections discussing astrogliosis do not report a GS decrease. The copy therefore does not verify the part attributed to this source. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Reactive astroglia increases trophic support, glutamate uptake, isolates lesioned areas favoring regeneration, activates immune pathways, and promotes BBB repair.

    “Although reactive astroglia increases trophic support and glutamate uptake, isolates lesioned areas favoring regeneration, activates immune pathways, and promotes BBB repair [38, 43, 45, 46, 47], astrocytes can become dysfunctional and acquire cytotoxic potential under prolonged stress [38, 43].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [47]

  • Under this context, astroglial death increases.

    “Under this context, astroglial death increases [28, 47].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [47]

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Cited by

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Authors
Verkhratsky, A.
Affiliations
Ikerbasque (ES)
Corresponding author
Verkhratsky, Alexei
ORCID
Verkhratsky, Alexei
Venue
Cold Spring Harbor Perspectives in Biology
Publisher
Cold Spring Harbor Laboratory
Published
2019-05-20
Volume
11
Issue
7
Pages
a035188
ISSN
1943-0264 (ISSN-L)
DOI
10.1101/cshperspect.a035188
PMC
PMC6601464
OpenAlex
W2946201788
Cited by
99
References
16
Citations by year
2026: 16 · 2025: 14 · 2024: 14 · 2023: 13 · 2022: 15 · 2021: 13 · 2020: 11 · 2019: 3
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
astrocytes, calcium signaling, brain aging, Alzheimer's disease, reactive astrogliosis, calcium oscillations, calcium waves, endoplasmic reticulum calcium release, amyloid plaques, entorhinal cortex, prefrontal cortex, neurodegeneration
MeSH terms
Aging, Alzheimer Disease, Astrocytes, Brain, Calcium, Humans, Calcium Signaling

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