Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment.
CSF1R
cerebrovascular disease
hypoperfusion
microglia
vascular cognitive impairment
white matter
Journal
Glia
ISSN: 1098-1136
Titre abrégé: Glia
Pays: United States
ID NLM: 8806785
Informations de publication
Date de publication:
Feb 2024
Feb 2024
Historique:
revised:
27
09
2023
received:
02
06
2023
accepted:
04
10
2023
medline:
17
12
2023
pubmed:
1
11
2023
entrez:
1
11
2023
Statut:
ppublish
Résumé
White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.
Substances chimiques
Receptors, Colony-Stimulating Factor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
375-395Subventions
Organisme : Medical Research Council
ID : G1002605
Pays : United Kingdom
Organisme : Alzheimer's Society
ID : 290 (AS-PG-15b-018)
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L003384/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G108/613
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L016400/1
Pays : United Kingdom
Organisme : Alzheimer's Society
ID : 228 (AS-DTC-201)
Pays : United Kingdom
Informations de copyright
© 2023 The Authors. GLIA published by Wiley Periodicals LLC.
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