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

Yousef, Hanadie; Czupalla, Cathrin J.; Lee, Davis P.; 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 A.; Merkel, Taylor; Körbelin, Jakob; Schwaninger, Markus; Buckwalter, Marion S; Quake, Stephen R.; Butcher, Eugene C.; Wyss-Coray, Tony

doi:10.1038/s41591-019-0440-4

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

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Author(s): Hanadie Yousef ¹ ^, ² , Cathrin J. Czupalla ² ^, ³ ^, ⁶ , Davis Lee ¹ ^, ² , Michelle B. Chen ⁴ , Ashley N. Burke ¹ ^, ² , Kristy A. Zera ¹ , Judith Zandstra ¹ ^, ² , Elisabeth Berber ¹ ^, ² , Benoit Lehallier ¹ ^, ² , Vidhu Mathur ¹ ^, ² , Ramesh V. Nair ⁵ , Liana N. Bonanno ¹ ^, ² , Andrew C. Yang ¹ ^, ⁴ , Todd Peterson ¹ , Husein Hadeiba ³ ^, ⁶ , Taylor Merkel ¹ ^, ² , Jakob Körbelin ⁷ , Markus Schwaninger ⁸ , Marion S. Buckwalter ¹ ^, ⁹ , Stephen R. Quake ⁴ ^, ¹⁰ , Eugene C. Butcher ² ^, ³ ^, ⁶ , Tony Wyss-Coray ¹ ^, ² ^, ⁶ ^, ⁹

Publication date (Electronic): 13 May 2019

Journal: Nature medicine

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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 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, the shed, soluble form of VCAM1 is prominently increased in plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and young mouse hippocampi. Systemic anti-VCAM1 antibody or genetic ablation of VCAM1 in BECs counteracts the detrimental effects of aged plasma on young brains and reverses aging aspects including microglial reactivity and cognitive deficits in old mouse brains. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier (BBB) as a possible target to treat age-related neurodegeneration.

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Most cited references 54

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Object recognition test in mice.

Marianne Leger, Anne Quiedeville, Valentine Bouet … (2013)

The object recognition test is now among the most commonly used behavioral tests for mice. A mouse is presented with two similar objects during the first session, and then one of the two objects is replaced by a new object during a second session. The amount of time taken to explore the new object provides an index of recognition memory. As more groups have used the protocol, the variability of the procedures used in the object recognition test has increased steadily. This protocol provides a necessary standardization of the procedure. This protocol reduces inter-individual variability with the use of a selection criterion based on a minimal time of exploration for both objects during each session. In this protocol, we describe the three most commonly used variants, containing long (3 d), short (1 d) or no habituation phases. Thus, with a short intersession interval (e.g., 6 h), this procedure can be performed in 4, 2 or 1 d, respectively, according to the duration of the habituation phase. This protocol should allow for the comparison of results from different studies, while permitting adaption of the protocol to the constraints of the experimenter.

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Ageing, neurodegeneration and brain rejuvenation.

Tony Wyss-Coray (2016)

Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of the essence of being. Ageing, which is fundamental to neurodegeneration and dementia, affects every organ in the body and seems to be encoded partly in a blood-based signature. Indeed, factors in the circulation have been shown to modulate ageing and to rejuvenate numerous organs, including the brain. The discovery of such factors, the identification of their origins and a deeper understanding of their functions is ushering in a new era in ageing and dementia research.

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Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

Saul Villeda, Kristopher E Plambeck, Jinte Middeldorp … (2014)

As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9502015

Journal ID (pubmed-jr-id): 8791

Journal ID (nlm-ta): Nat Med

Journal ID (iso-abbrev): Nat. Med.

Title: Nature medicine

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Nihms-submitted: 20 March 2019

Publication date (Electronic): 13 May 2019

Publication date (Print): June 2019

Publication date PMC-release: 13 November 2019

Volume: 25

Issue: 6

Pages: 988-1000

Affiliations

[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 ]Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA, USA

[5 ]Stanford Center for Genomics and Personalized Medicine, Stanford, CA, USA

[6 ]Palo Alto Veterans Institute for Research, Palo Alto, CA 94304

[7 ]Department of Oncology, Hematology and Stem Cell Transplantation with Section Pneumology, 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

Author notes

Correspondence: twc@ 123456stanford.edu

AUTHOR CONTRIBUTIONS

H.Y. and T.W.-C. designed research. H.Y., C.J.C, and D.L. isolated BECs. H.Y. and C.J.C performed and analyzed flow cytometry. H.Y. and A.N.B. performed in vitro experiments. H.Y., A.N.B., J.Z., D.L., T.M. performed staining/microscopy analysis and cell counts. H.Y., A.N.B., and J.Z. performed ELISAs and western blots. H.Y. and C.J.C. performed tissue dissections. H.Y., C.J.C., and D.L. performed plasma injections. H.Y. and L.N.B. performed parabiosis. M.S. provided Slco1c1-Cre ^ERT2 breeding pair. B.L. analyzed human proteomic data. H.H. helped with the design of the immune phenotyping panel and flow cytometry staining and analysis of PBMCs. K.A.Z., H.Y., D.L., C.J.C., performed behavior studies. M.S.B., T.P., and K.A.Z. carried out Barnes maze and novel object recognition studies. H.Y. and D.L. sectioned, stained, and analyzed neuroinflammation in the peri-infarct region. A.C.Y., D.L., V.M., and H.Y. performed and analyzed the BBB permeability with dextran experiments. V.M., A.N.B., D.L., and M.B.C edited the manuscript. C.J.C. and E.C.B. helped with experimental design and edited the manuscript. C.J.C developed protocols for BEC isolation, cultivation and flow cytometry following LPS stimulation. H.Y. and E.B. performed bulk RNAseq experiment. H.Y., M.B.C, and D.L. performed single cell RNAseq experiment. S.R.Q supervised scRNAseq data collection and analysis and reviewed the manuscript. H.Y., R.V.N. and B.L. and E.B. analyzed bulk transcriptomic data. M.B.C and H.Y. analyzed single cell transcriptomic data. J.K. provided a BBB-specific AAV vector plasmid. H.Y. analyzed data and generated the figures. H.Y. and T.W.-C. wrote the manuscript. T.W.-C. supervised the study.

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Manuscript ID: NIHMS1523758

DOI: 10.1038/s41591-019-0440-4

PMC ID: 6642642

PubMed ID: 31086348

SO-VID: af2d896b-f777-42dc-a283-2c21bc71cfdc

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

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Abstract

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Nanoparticles to cross the blood-brain barrier (BBB)

Most cited references 54

Object recognition test in mice.

Ageing, neurodegeneration and brain rejuvenation.

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

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