Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1

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 transcrip...

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Bibliographic Details
Published in:Nature medicine Vol. 25; no. 6; pp. 988 - 1000
Main Authors: Yousef, Hanadie, Czupalla, Cathrin J, Lee, Davis, Chen, Michelle B, Burke, Ashley N, Zera, Kristy A, Zandstra, Judith, Berber, Elisabeth, Lehallier, Benoit, Mathur, Vidhu, Nair, Ramesh V, Bonanno, Liana N, Yang, Andrew C, Peterson, Todd, Hadeiba, Husein, Merkel, Taylor, Körbelin, Jakob, Schwaninger, Markus, Buckwalter, Marion S, Quake, Stephen R, Butcher, Eugene C, Wyss-Coray, Tony
Format: Journal Article
Language:English
Published: United States Nature Publishing Group 01.06.2019
Subjects:
Ablation
Adolescent
Adult
Aged
Aging
Aging - blood
Aging - immunology
Aging - metabolism
Animals
Antibodies
Blood
Blood-Brain Barrier - immunology
Blood-Brain Barrier - metabolism
Brain
Brain - cytology
Brain - metabolism
Cell adhesion
Cell adhesion & migration
Cell adhesion molecules
Cell interactions
Cells, Cultured
Cognition
Cognitive ability
Endothelial cells
Endothelial Cells - metabolism
Female
Gene Deletion
Hippocampus
Hippocampus - cytology
Hippocampus - metabolism
Humans
Immune system
Inflammation
Inflammation Mediators - metabolism
Male
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Microglia
Microglia - metabolism
Neural Stem Cells - cytology
Neural Stem Cells - metabolism
Neurodegeneration
Precursors
Transcription
Vascular cell adhesion molecule 1
Vascular Cell Adhesion Molecule-1 - blood
Vascular Cell Adhesion Molecule-1 - genetics
Vascular Cell Adhesion Molecule-1 - metabolism
Young Adult
ISSN:1078-8956, 1546-170X, 1546-170X
Online Access:Get full text
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Summary: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.
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ISSN:1078-8956
1546-170X
1546-170X
DOI:10.1038/s41591-019-0440-4