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

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 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.

The Impact of Ageing on the CNS Immune Response in Alzheimer’s Disease

“…T regulatory (Treg) cells have also been implicated in contributing to the pathogenesis of AD, albeit their exact role remains to be fully elucidated. For example, transient depletion of Treg cells have been associated with an IFNg-dependent systemic immune response characterized by the peripheral recruitment of monocytes via the choroid plexus, and this process in turn was associated with increased Ab plaque clearance and improvement in cognition in mice models of AD (58,59). However, current studies showing conflicting evidence on the role of Treg cells as either beneficial or detrimental disallows any concrete conclusions on their contributions to AD pathogenesis (59)(60)(61)(62).…”

“…In addition to these lymphatic vessels, the meninges serve as an important neuroimmune interface for modulating local immune responses. For example, the loss of C-C chemokine receptor (CCR) 7 in transgenic mice led to increased meningeal Treg responses, attenuated meningeal effector T cell responses, and cognitive deficits (59).…”

Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke

“…The loss of CCR7 expression leads to diminished IFN-γ-producing CD4 + T-cells, effector T-cells, and cognitive ability but increased meningeal Treg responses. When anti-CD25 antibodies were given to aged mice, cognitive function was improved, with a reduction of Treg responses in meninges and dCLNs [386].…”

Meningeal Lymphatics: An Immune Gateway for the Central Nervous System

“…In AD, it is well accepted that the mLVs are important for the drainage of amyloid beta (Aβ) and tau [ 50 , 51 , 52 , 53 ]. Da Mesquita et al have shown that the impairment of the mLVs leads to increased accumulation of Aβ plaques and worse cognitive performance.…”