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 Quake; Eugene C Butcher; Tony Wyss-Coray

doi:10.1038/s41591-019-0440-4

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

Institute of Experimental and Clinical Pharmacology and Toxicology

356 Citations (Scopus)

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 language	English
Journal	Nature Medicine
Volume	25
Issue number	6
Pages (from-to)	988-1000
Number of pages	13
ISSN	1078-8956
DOIs	https://doi.org/10.1038/s41591-019-0440-4
Publication status	Published - 01.06.2019

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SDG 3 Good Health and Well-being

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

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Yousef, H., Czupalla, C. J., Lee, D., Chen, M. B., Burke, A. N., Zera, K. A., Zandstra, J., Berber, E., Lehallier, B., Mathur, V., Nair, R. V., Bonanno, L. N., Yang, A. C., Peterson, T., Hadeiba, H., Merkel, T., Körbelin, J., Schwaninger, M., Buckwalter, M. S., ... Wyss-Coray, T. (2019). Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nature Medicine, 25(6), 988-1000. https://doi.org/10.1038/s41591-019-0440-4

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title = "Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1",

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.",

author = "Hanadie Yousef and Czupalla, \{Cathrin J\} and Davis Lee and Chen, \{Michelle B\} and Burke, \{Ashley N\} and Zera, \{Kristy A\} and Judith Zandstra and Elisabeth Berber and Benoit Lehallier and Vidhu Mathur and Nair, \{Ramesh V\} and Bonanno, \{Liana N\} and Yang, \{Andrew C\} and Todd Peterson and Husein Hadeiba and Taylor Merkel and Jakob K{\"o}rbelin and Markus Schwaninger and Buckwalter, \{Marion S\} and Quake, \{Stephen R\} and Butcher, \{Eugene C\} and Tony Wyss-Coray",

year = "2019",

month = jun,

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doi = "10.1038/s41591-019-0440-4",

language = "English",

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Yousef, H, Czupalla, CJ, Lee, D, Chen, MB, Burke, AN, Zera, KA, Zandstra, J, Berber, E, Lehallier, B, Mathur, V, Nair, RV, Bonanno, LN, Yang, AC, Peterson, T, Hadeiba, H, Merkel, T, Körbelin, J, Schwaninger, M, Buckwalter, MS, Quake, SR, Butcher, EC & Wyss-Coray, T 2019, 'Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1', Nature Medicine, vol. 25, no. 6, pp. 988-1000. https://doi.org/10.1038/s41591-019-0440-4

TY - JOUR

T1 - Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1

AU - Yousef, Hanadie

AU - Czupalla, Cathrin J

AU - Lee, Davis

AU - Chen, Michelle B

AU - Burke, Ashley N

AU - Zera, Kristy A

AU - Zandstra, Judith

AU - Berber, Elisabeth

AU - Lehallier, Benoit

AU - Mathur, Vidhu

AU - Nair, Ramesh V

AU - Bonanno, Liana N

AU - Yang, Andrew C

AU - Peterson, Todd

AU - Hadeiba, Husein

AU - Merkel, Taylor

AU - Körbelin, Jakob

AU - Schwaninger, Markus

AU - Buckwalter, Marion S

AU - Quake, Stephen R

AU - Butcher, Eugene C

AU - Wyss-Coray, Tony

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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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UR - http://www.mendeley.com/research/aged-blood-impairs-hippocampal-neural-precursor-activity-activates-microglia-via-brain-endothelial-c

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DO - 10.1038/s41591-019-0440-4

M3 - Journal articles

C2 - 31086348

SN - 1078-8956

VL - 25

SP - 988

EP - 1000

JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -

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

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