Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology.

Autor:	Da Mesquita S; Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. damesquita@mayo.edu kipnis@wustl.edu., Herz J; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA., Wall M; Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA., Dykstra T; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA., de Lima KA; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA., Norris GT; Department of Immunology, University of Washington, Seattle, WA 98109, USA., Dabhi N; Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA., Kennedy T; Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA., Baker W; Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA., Kipnis J; Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. damesquita@mayo.edu kipnis@wustl.edu.; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2021 May 21; Vol. 7 (21). Date of Electronic Publication: 2021 May 21 (Print Publication: 2021).
DOI:	10.1126/sciadv.abe4601
Abstrakt:	Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)-dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer's disease-like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze:	MEDLINE
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