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Cited by 80Neuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury and Neurovascular DisturbancesSpinal Cord Injury Research

Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration

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Das, Sudeshna, Li, Zhaozhi, Noori, Ayush, Hyman, Bradley T., Serrano-Pozo, Alberto·2020·Journal of Neuroinflammation
DOI 10.1186/s12974-020-01898-yPMC PMC7393869
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Abstract

Background: Neuronal damage in acute CNS injuries and chronic neurodegenerative diseases is invariably accompanied by an astrocyte reaction in both mice and humans. However, whether and how the nature of the CNS insult—acute versus chronic—influences the astrocyte response, and whether astrocyte transcriptomic changes in these mouse models faithfully recapitulate the astrocyte reaction in human diseases remains to be elucidated. We hypothesized that astrocytes set off different transcriptomic programs in response to acute versus chronic insults, besides a shared “pan-injury” signature common to both types of conditions, and investigated the presence of these mouse astrocyte signatures in transcriptomic studies from human neurodegenerative diseases. Methods: We performed a meta-analysis of 15 published astrocyte transcriptomic datasets from mouse models of acute injury ( n = 6) and chronic neurodegeneration ( n = 9) and identified pan-injury, acute, and chronic signatures, with both upregulated (UP) and downregulated (DOWN) genes. Next, we investigated these signatures in 7 transcriptomic datasets from various human neurodegenerative diseases. Results: In mouse models, the number of UP/DOWN genes per signature was 64/21 for pan-injury and 109/79 for acute injury, whereas only 13/27 for chronic neurodegeneration. The pan-injury-UP signature was represented by the classic cytoskeletal hallmarks of astrocyte reaction ( Gfap and Vim ), plus extracellular matrix (i.e., Cd44 , Lgals1, Lgals3, Timp1 ), and immune response (i.e., C3, Serping1, Fas, Stat1, Stat2, Stat3 ). The acute injury-UP signature was enriched in protein synthesis and degradation (both ubiquitin-proteasome and autophagy systems), intracellular trafficking, and anti-oxidant defense genes, whereas the acute injury-DOWN signature included genes that regulate chromatin structure and transcriptional activity, many of which are transcriptional repressors. The chronic neurodegeneration-UP signature was further enriched in astrocyte-secreted extracellular matrix proteins ( Lama4 , Cyr61 , Thbs4 ), while the DOWN signature included relevant genes such as Agl (glycogenolysis), S1pr1 (immune modulation), and Sod2 (anti-oxidant). Only the pan-injury-UP mouse signature was clearly present in some human neurodegenerative transcriptomic datasets. Conclusions: Acute and chronic CNS injuries lead to distinct astrocyte gene expression programs beyond their common astrocyte reaction signature. However, caution should be taken when extrapolating astrocyte transcriptomic findings from mouse models to human diseases.

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  • Only a subset, often a mix of A1 and A2 or pan-reactive transcripts, are upregulated in astrocytes from brains of study participants with HD or AD, or from several mouse models of acute injuries and chronic diseases of the CNS.

    “Importantly, only a subset, often a mix of A1 and A2 or pan-reactive transcripts, are upregulated in astrocytes from brains of study participants with HD74 or AD75,76, or from several mouse models of acute injuries and chronic diseases of the CNS42,69,76,77.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [77]

    The Results section on A1 and A2 signatures (page not provided) reports that A1, A2, and pan-reactive genes were generally upregulated across the mouse acute-injury and neurodegeneration models, supporting the mixed-signature portion of the claim. But the Results section on human validation says none of the three mouse signatures was clearly present in the two astrocyte-specific AD datasets; the AD concordance it found came from bulk-tissue datasets. Thus this source does not establish the claimed upregulation in astrocytes from people with AD. The HD portion is attached to a different citation. (LLM, conf=0.87)

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Authors
Das, S., Li, Z., Noori, A., Hyman, B. T., & Serrano-Pozo, A.
Affiliations
  • Harvard University (US)
  • Massachusetts General Hospital (US)
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2020-07-31
Volume
17
Issue
1
Pages
227-227
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-020-01898-y
PMC
PMC7393869
OpenAlex
W3046615650
Cited by
80
References
122
Citations by year
2026: 4 · 2025: 7 · 2024: 14 · 2023: 16 · 2022: 17 · 2021: 17 · 2020: 5
FWCI
1.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Alzheimer's Association (AACF-17-524184)
  • National Institute on Aging (1K08AG064039, P30AG062421)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
Keywords
astrocyte transcriptome, neurodegeneration, mouse model, extracellular matrix, glial fibrillary acidic protein, vimentin, oxidative stress, autophagy, ubiquitin-proteasome system, immune response, transcriptional repressor, astrocyte reprogramming, translational validity
MeSH terms
Animals, Astrocytes, Glial Fibrillary Acidic Protein, Nerve Degeneration, Neurons, Gene Expression Profiling, Mice, Transcriptome

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