Two forms of CX3CL1 display differential activity and rescue cognitive deficits in CX3CL1 knockout mice.
Aging
CX3CL1
Cognition
Fractalkine
Long-term potentiation
Microglia
Neurodegeneration
Neurogenesis
Neuroinflammation
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
14 May 2020
14 May 2020
Historique:
received:
10
02
2020
accepted:
24
04
2020
entrez:
16
5
2020
pubmed:
16
5
2020
medline:
1
4
2021
Statut:
epublish
Résumé
Fractalkine (CX3CL1; FKN) is a chemokine expressed by neurons that mediates communication between neurons and microglia. By regulating microglial activity, CX3CL1 can mitigate the damaging effects of chronic microglial inflammation within the brain, a state that plays a major role in aging and neurodegeneration. CX3CL1 is present in two forms, a full-length membrane-bound form and a soluble cleaved form (sFKN), generated by a disintegrin and metalloproteinase (ADAM) 10 or 17. Levels of sFKN decrease with aging, which could lead to enhanced inflammation, deficits in synaptic remodeling, and subsequent declines in cognition. Recently, the idea that these two forms of CX3CL1 may display differential activities within the CNS has garnered increased attention, but remains unresolved. Here, we assessed the consequences of CX3CL1 knockout (CX3CL1 CX3CL1 These results are the first to demonstrate that CX3CL1 knockout causes significant cognitive deficits that can be rescued by treatment with sFKN and only partially rescued with mFKN. This suggests that treatments that restore signaling of soluble forms of CX3CL1 may be a viable therapeutic option for aging and disease.
Sections du résumé
BACKGROUND
BACKGROUND
Fractalkine (CX3CL1; FKN) is a chemokine expressed by neurons that mediates communication between neurons and microglia. By regulating microglial activity, CX3CL1 can mitigate the damaging effects of chronic microglial inflammation within the brain, a state that plays a major role in aging and neurodegeneration. CX3CL1 is present in two forms, a full-length membrane-bound form and a soluble cleaved form (sFKN), generated by a disintegrin and metalloproteinase (ADAM) 10 or 17. Levels of sFKN decrease with aging, which could lead to enhanced inflammation, deficits in synaptic remodeling, and subsequent declines in cognition. Recently, the idea that these two forms of CX3CL1 may display differential activities within the CNS has garnered increased attention, but remains unresolved.
METHODS
METHODS
Here, we assessed the consequences of CX3CL1 knockout (CX3CL1
RESULTS
RESULTS
CX3CL1
CONCLUSIONS
CONCLUSIONS
These results are the first to demonstrate that CX3CL1 knockout causes significant cognitive deficits that can be rescued by treatment with sFKN and only partially rescued with mFKN. This suggests that treatments that restore signaling of soluble forms of CX3CL1 may be a viable therapeutic option for aging and disease.
Identifiants
pubmed: 32410624
doi: 10.1186/s12974-020-01828-y
pii: 10.1186/s12974-020-01828-y
pmc: PMC7227354
doi:
Substances chimiques
Chemokine CX3CL1
0
Cx3cl1 protein, mouse
0
Protein Isoforms
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
157Subventions
Organisme : NIA NIH HHS
ID : AG044919
Pays : United States
Organisme : U.S. Department of Veterans Affairs
ID : IK6BX004214
Organisme : BLRD VA
ID : IK6 BX004214
Pays : United States
Organisme : BLRD VA
ID : I01 BX003421
Pays : United States
Organisme : U.S. Department of Veterans Affairs
ID : I01BX003421
Organisme : NIA NIH HHS
ID : R01 AG044919
Pays : United States
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