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Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and ß-amyloid pathology.
Da Mesquita, Sandro; Herz, Jasmin; Wall, Morgan; Dykstra, Taitea; de Lima, Kalil Alves; Norris, Geoffrey T; Dabhi, Nisha; Kennedy, Tatiana; Baker, Wendy; Kipnis, Jonathan.
Afiliação
  • 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.
  • Wall M; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
  • Dykstra T; Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA.
  • de Lima KA; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.
  • Norris GT; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
  • Dabhi N; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.
  • Kennedy T; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
  • Baker W; Department of Immunology, University of Washington, Seattle, WA 98109, USA.
  • Kipnis J; Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA.
Sci Adv ; 7(21)2021 05.
Article em En | MEDLINE | ID: mdl-34020948
ABSTRACT
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 ß-amyloid (Aß) 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 Aß 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.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Risk_factors_studies Idioma: En Revista: Sci Adv Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Risk_factors_studies Idioma: En Revista: Sci Adv Ano de publicação: 2021 Tipo de documento: Article