A major challenge in the field of neurodegenerative diseases and brain aging is to identify the body's intrinsic mechanism that could sense the central nervous system (CNS) damage early and protect the brain from neurodegeneration. Accumulating evidence suggests that disease-associated microglia (DAM), a recently identified subset of CNS resident macrophages found at sites of neurodegeneration, might play such a protective role. Here, we propose that microglia are endowed with a dedicated sensory mechanism, which includes the Trem2 signaling pathway, to detect damage within the CNS in the form of neurodegeneration-associated molecular patterns (NAMPs). Combining data from transcriptional analysis of DAM at single-cell level and from human genome-wide association studies (GWASs), we discuss potential function of different DAM pathways in the diseased brain and outline how manipulating DAM may create new therapeutic opportunities.

Age-associated cognitive decline is affected by factors produced inside and outside the brain. We found in aged mice and humans, that the choroid plexus (CP), an epithelial interface between the brain and the circulation, shows a type I interferon (IFN-I)-dependent expression profile, often associated with anti-viral responses. This signature was induced by brain-derived signals present in the cerebrospinal fluid of aged mice. Blocking IFN-I signaling within the brain of cognitively-impaired aged mice, using IFN-I receptor neutralizing antibody, led to partial restoration of cognitive function and hippocampal neurogenesis, and reestablished IFN-II-dependent CP activity, lost in aging. Our data identify an aging-induced IFN-I signature at the CP, and demonstrate its negative influence on brain function, thereby suggesting a potential target for therapeutic intervention for age-related cognitive decline.

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Alzheimer's disease (AD) is a neurodegenerative disorder in which chronic neuroinflammation contributes to disease escalation. Nevertheless, while immunosuppressive drugs have repeatedly failed in treating this disease, recruitment of myeloid cells to the CNS was shown to play a reparative role in animal models. Here we show, using the 5XFAD AD mouse model, that transient depletion of Foxp3+ regulatory T cells (Tregs), or pharmacological inhibition of their activity, is followed by amyloid-β plaque clearance, mitigation of the neuroinflammatory response and reversal of cognitive decline. We further show that transient Treg depletion affects the brain's choroid plexus, a selective gateway for immune cell trafficking to the CNS, and is associated with subsequent recruitment of immunoregulatory cells, including monocyte-derived macrophages and Tregs, to cerebral sites of plaque pathology. Our findings suggest targeting Treg-mediated systemic immunosuppression for treating AD.

The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions.