Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1.
Adolescent
Adult
Aged
Aging
/ blood
Animals
Blood-Brain Barrier
/ immunology
Brain
/ cytology
Cells, Cultured
Endothelial Cells
/ metabolism
Female
Gene Deletion
Hippocampus
/ cytology
Humans
Inflammation Mediators
/ metabolism
Male
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Microglia
/ metabolism
Neural Stem Cells
/ cytology
Vascular Cell Adhesion Molecule-1
/ blood
Young Adult
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
30
08
2017
accepted:
11
03
2019
pubmed:
16
5
2019
medline:
16
7
2019
entrez:
16
5
2019
Statut:
ppublish
Résumé
An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.
Identifiants
pubmed: 31086348
doi: 10.1038/s41591-019-0440-4
pii: 10.1038/s41591-019-0440-4
pmc: PMC6642642
mid: NIHMS1523758
doi:
Substances chimiques
Inflammation Mediators
0
Vascular Cell Adhesion Molecule-1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
988-1000Subventions
Organisme : NIA NIH HHS
ID : R01 AG045034
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI047822
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI109452
Pays : United States
Organisme : NIA NIH HHS
ID : F32 AG051330
Pays : United States
Organisme : NIA NIH HHS
ID : DP1 AG053015
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001085
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM037734
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM120007
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR003142
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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