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Cited by 66FOXO transcription factor regulationAlzheimer's disease research and treatmentsRedox biology and oxidative stress

The nuclear retention of transcription factor FOXO3a correlates with a DNA damage response and increased glutamine synthetase expression by astrocytes suggesting a neuroprotective role in the ageing brain

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Fluteau, Adeline, Ince, Paul G., Minett, Thais, Matthews, Fiona E., Brayne, Carol, Garwood, Claire J., Ratcliffe, Laura E., Morgan, Sarah +4 more·2015·Neuroscience Letters
DOI 10.1016/j.neulet.2015.10.001PMC PMC4674771
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Abstract

The accumulation of reactive oxygen species leading to oxidative damage and cell death plays an important role in a number of neurodegenerative disorders. FOXO3a, the main isoform of FOXO transcription factors, mediates the cellular response to oxidative stress by regulating the expression of genes involved in DNA repair and glutamine metabolism, including glutamine synthetase (GS). Immunohistochemical investigation of the population-based neuropathology cohort of the Medical Research Council's Cognitive Function and Ageing Study (MRC CFAS) demonstrates that nuclear retention of FOXO3a significantly correlates with a DNA damage response and with GS expression by astrocytes. Furthermore, we show that GS expression correlates with increasing Alzheimer-type pathology in this ageing cohort. Our findings suggest that in response to oxidative stress, the nuclear retention of FOXO3a in astrocytes upregulates expression of GS as a neuroprotective mechanism. However, the activity of GS may be compromised by increasing levels of oxidative stress in the ageing brain resulting in dysfunctional enzyme activity, neuronal excitotoxic damage and cognitive impairment.

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  • Astroglial reactivity impacts astrocyte-dependent glutamate homeostasis.

    “As astroglial reactivity impacts astrocyte‐dependent glutamate homeostasis [36, 94, 95, 96, 97]”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [95]

    The Introduction and Discussion describe astrocytes’ role in glutamate homeostasis and suggest that their response to oxidative stress can alter glutamine synthetase expression. But the Results report no significant correlation between glutamine-synthetase-positive astrocytes and astrogliosis, so this paper does not establish that astroglial reactivity itself impacts glutamate homeostasis. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • GS can be upregulated by astrocytes and expressed by neurons in response to aging and AD.

    “it has also been shown that GS can be upregulated by astrocytes [95] and expressed by neurons [24] in response to aging and AD.”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [95]

    The Results report that GS-positive astrocytes increased with measures of Alzheimer-type pathology, supporting the part attributed to this source. They also state that GS was not significantly related to age, so upregulation in response to aging is not established. The neuronal-expression claim has a separate citation and is not assessed here. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Fluteau, A., Ince, P. G., Minett, T., Matthews, F. E., Brayne, C., Garwood, C. J., Ratcliffe, L. E., Morgan, S., Heath, P. R., Shaw, P. J., Wharton, S. B., & Simpson, J. E.
Affiliations
  • MRC Human Genetics Unit (GB)
  • University of Sheffield (GB)
  • University of Manchester (GB)
  • University of Cambridge (GB)
Corresponding author
Simpson, Julie E.
ORCID
Venue
Neuroscience Letters
Publisher
Elsevier BV
Published
2015-11
Volume
609
Pages
11-17
ISSN
0304-3940 (ISSN-L)
DOI
10.1016/j.neulet.2015.10.001
PMC
PMC4674771
OpenAlex
W1860448409
Cited by
66
References
7
Citations by year
2026: 5 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 2
FWCI
2.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroscience Letters (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Repository@Hull (Worktribe) (University of Hull) (submittedVersion, cc-by)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
Medical Research Council (MRJ004308/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
FOXO3, nuclear retention, astrocytes, glutamine synthetase, DNA damage response, oxidative stress, brain aging, Alzheimer's disease pathology, neuroprotection, glutamine metabolism, reactive oxygen species, cognitive impairment, excitotoxicity
MeSH terms
Forkhead Box Protein O3, Aged, Aged, 80 and over, Alzheimer Disease, Astrocytes, Brain, Cell Nucleus, Dementia, DNA Damage, Female, Gliosis, Glutamate-Ammonia Ligase, Humans, Male, Temporal Lobe, Forkhead Transcription Factors

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