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Nat Med. 2019 Jun;25(6):988-1000. doi: 10.1038/s41591-019-0440-4. Epub 2019 May 13.

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

Author information

1
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
2
VA Palo Alto Health Care System, Palo Alto, CA, USA.
3
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
4
Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
5
Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA, USA.
6
Stanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA.
7
Section of Pneumology, Department of Oncology, Hematology and Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
8
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lubeck, Lubeck, Germany.
9
Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
10
Chan Zuckerberg Biohub, Stanford, CA, USA.
11
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.
12
VA Palo Alto Health Care System, Palo Alto, CA, USA. twc@stanford.edu.
13
Palo Alto Veterans Institute for Research, Palo Alto, CA, USA. twc@stanford.edu.
14
Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. twc@stanford.edu.

Abstract

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.

PMID:
31086348
PMCID:
PMC6642642
DOI:
10.1038/s41591-019-0440-4
[Indexed for MEDLINE]
Free PMC Article

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