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Meta‐analysis of mouse transcriptomic studies supports a context‐dependent astrocyte reaction in acute CNS injury versus neurodegeneration
Author(s) -
Das Sudeshna,
Li Zhaozhi,
Noori Ayush,
Hyman Bradley T.,
SerranoPozo Alberto
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.040699
Subject(s) - neurodegeneration , astrocyte , transcriptome , biology , microbiology and biotechnology , neuroscience , medicine , pathology , gene expression , central nervous system , gene , genetics , disease
Background Neuronal damage in both acute central nervous system (CNS) injuries and chronic neurodegenerative diseases is invariably accompanied by an astrocyte reaction, which has traditionally been depicted with GFAP immunohistochemistry. However, whether and how the nature of the CNS insult —acute versus chronic — influences the astrocyte response is unknown. We hypothesized that astrocytes set off different transcriptomic programs in response to acute versus chronic insults, in addition to a shared “pan‐reactive” signature common to both types of conditions. Method We performed a meta‐analysis of 15 publicly available astrocyte transcriptomic datasets from acute injury (n=6) and chronic neurodegeneration (n=9) mouse models. We identified a pan‐reactive, acute injury‐ and chronic neurodegeneration‐specific signatures, with both up‐regulated (UP) and down‐regulated (DOWN) genes. Result The number of UP/DOWN genes for each signature was: 67/21 for pan‐reactive, 109/79 for acute injury, whereas only 13/27 for chronic neurodegeneration. The pan‐reactive‐UP signature was represented by the classic cytoskeletal hallmarks of astrocyte reaction (i.e. Gfap, Vim ), plus extracellular matrix (i.e. Cd44, Lgals1, Lgals3, Timp1) , and immune response genes (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), and anti‐oxidant defense genes, whereas the acute injury‐DOWN signature included genes that regulate chromatin structure and transcriptional activity, many of which were transcriptional repressors. The chronic neurodegeneration‐UP signature was further enriched in astrocyte‐secreted extracellular matrix proteins ( Lama4, Cyr61, Thbs4 ), while the DOWN set included genes such as Agl (glycogenolysis) , S1pr1 (immune modulation) and Sod2 (antioxidant). Conclusion We conclude that acute and chronic injuries to the CNS are associated with distinct astrocyte gene expression programs beyond their common astrocyte reaction signature.