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

Hanadie Yousef, Cathrin J Czupalla, Davis Lee, Michelle B Chen, Ashley N Burke, Kristy A Zera, Judith Zandstra, Elisabeth Berber, Benoit Lehallier, Vidhu Mathur, Ramesh V Nair, Liana N Bonanno, Andrew C Yang, Todd Peterson, Husein Hadeiba, Taylor Merkel, Jakob Körbelin, Markus Schwaninger, Marion S Buckwalter, Stephen R QuakeEugene C Butcher, Tony Wyss-Coray

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.

Original languageEnglish
JournalNature Medicine
Volume25
Issue number6
Pages (from-to)988-1000
Number of pages13
ISSN1078-8956
DOIs
Publication statusPublished - 01.06.2019

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

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