Summary The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69 + CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. Video Abstract

The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.

SummaryThe role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfbret/ret mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit β-amyloid peptide (Aβ) formation in Alzheimer's disease (AD). ADAM10 also plays a critical role in regulating functional membrane proteins at the synapse. Using human hippocampal homogenates, we found that ADAM10 removal from the plasma membrane was mediated by clathrin-dependent endocytosis. Additionally, we identified the clathrin adaptor AP2 as an interacting partner of a previously uncharacterized atypical binding motif in the ADAM10 C-terminal domain. This domain was required for ADAM10 endocytosis and modulation of its plasma membrane levels. We found that the ADAM10/AP2 association was increased in the hippocampi of AD patients compared with healthy controls. Long-term potentiation (LTP) in hippocampal neuronal cultures induced ADAM10 endocytosis through AP2 association and decreased surface ADAM10 levels and activity. Conversely, long-term depression (LTD) promoted ADAM10 synaptic membrane insertion and stimulated its activity. ADAM10 interaction with the synapse-associated protein-97 (SAP97) was necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced changes in spine morphogenesis. These data identify and characterize a mechanism controlling ADAM10 localization and activity at excitatory synapses that is relevant to AD pathogenesis.

Neurodegenerative diseases of the central nervous system (CNS) are characterized by progressive neuronal death and neurological dysfunction, leading to increased disability and a loss of cognitive or motor functions. Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis have neurodegeneration as a primary feature. However, in other CNS diseases such as multiple sclerosis, stroke, traumatic brain injury, and spinal cord injury, neurodegeneration follows another insult, such as demyelination or ischaemia. Although there are different primary causes to these diseases, they all share a hallmark of neuroinflammation. Neuroinflammation can occur through the activation of resident immune cells such as microglia, cells of the innate and adaptive peripheral immune system, meningeal inflammation and autoantibodies directed toward components of the CNS. Despite chronic inflammation being pathogenic in these diseases, local inflammation after insult can also promote endogenous regenerative processes in the CNS, which are key to slowing disease progression. The normal aging process in the healthy brain is associated with a decline in physiological function, a steady increase in levels of neuroinflammation, brain shrinkage, and memory deficits. Likewise, aging is also a key contributor to the progression and exacerbation of neurodegenerative diseases. As there are associated co-morbidities within an aging population, pinpointing the precise relationship between aging and neurodegenerative disease progression can be a challenge. The CNS has historically been considered an isolated, “immune privileged” site, however, there is mounting evidence that adaptive immune cells are present in the CNS of both healthy individuals and diseased patients. Adaptive immune cells have also been implicated in both the degeneration and regeneration of the CNS. In this review, we will discuss the key role of the adaptive immune system in CNS degeneration and regeneration, with a focus on how aging influences this crosstalk.

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. While remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared to their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, while cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.

Activation of retinoid X receptor γ and vitamin D receptor (VDR) heterodimer via vitamin D enhances oligodendrocyte progenitor differentiation, whereas blocking VDR impairs differentiation and myelination ex vivo.

Pathogenic mechanisms of T cells in several central nervous system (CNS) disorders are well-established. However, more recent studies have uncovered compelling beneficial roles of T cells in neurological diseases, ranging from tissue protection to regeneration. These divergent functions arise due to the diversity of T cell subsets, particularly CD4+ T cells. Here, we review the beneficial impact of T cell subsets in a range of neuroinflammatory and neurodegenerative diseases including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and CNS trauma. Both T cell-secreted mediators and direct cell contact-dependent mechanisms deliver neuroprotective, neuroregenerative and immunomodulatory signals in these settings. Understanding the molecular details of these beneficial T cell mechanisms will provide novel targets for therapeutic exploitation that can be applied to a range of neurological disorders.