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Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration

An Author Correction to this article was published on 13 March 2020

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Abstract

A rapidly ageing population and a limited therapeutic toolbox urgently necessitate new approaches to treat neurodegenerative diseases. Brain ageing, the key risk factor for neurodegeneration, involves complex cellular and molecular processes that eventually result in cognitive decline. Although cell-intrinsic defects in neurons and glia may partially explain this decline, cell-extrinsic changes in the systemic environment, mediated by blood, have recently been shown to contribute to brain dysfunction with age. Here, we review the current understanding of how systemic factors mediate brain ageing, how these factors are regulated and how we can translate these findings into therapies for neurodegenerative diseases.

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Fig. 1: A framework for understanding the effects of systemic factors on the brain.
Fig. 2: Effects of cytokines and chemokines on age-related brain dysfunction.

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Acknowledgements

This work was supported by a National Institutes of Health National Institute on Ageing (NIA) grant F30 AG055255 (J.P.), DP1 AG060638 (T.W.-C.), and the NOMIS Foundation (T.W.-C.).

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Both authors contributed equally to all aspects of the manuscript.

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Correspondence to John V. Pluvinage or Tony Wyss-Coray.

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T.W.-C. is a co-founder, shareholder and paid consultant of Alkahest, Inc., a company that develops treatments for CNS diseases based on the concept that circulatory factors regulate brain function. J.V.P. declares no competing interests.

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Glossary

Parabionts

Animals that share partial blood circulation with another animal via surgical anastomosis.

Type 2 T helper cell phenotype

CD4+ T cells that produce high levels of IL-4, IL-5 and IL-13, but little or no IFNγ, IL-2 or TNF. Canonically, these cells protect against multicellular parasites.

Caveolae-mediated transcytosis

A form of clathrin-independent endocytosis that facilitates non-specific transcytosis of extracellular molecules across the BBB, which are then trafficked across the cell in pH-neutral compartments called caveosomes.

Aptamer-based proteomics

A technique that uses short single-stranded oligonucleotides called aptamers to bind and identify proteins in a complex mixture with high affinity and specificity.

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Pluvinage, J.V., Wyss-Coray, T. Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration. Nat Rev Neurosci 21, 93–102 (2020). https://doi.org/10.1038/s41583-019-0255-9

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