Upper-Limb Paresis Severity Is Associated With Practice Dosage During Task-Oriented Training in Subacute Stroke-An Exploratory Secondary Analysis.

Aging is accompanied by progressive functional decline across multiple organ systems, but its impact on the brain is especially devastating, given the dysfunction wrought across key cognitive domains and the increased risk it poses for several neurological disorders. These changes reflect cumulative cellular, molecular, and structural perturbations, including loss of synaptic and myelin integrity, and neuroinflammation in vulnerable brain regions like the hippocampus. Understanding mechanisms that regulate aging in the hippocampus is thus essential for identifying new strategies to preserve or restore function across the lifespan and to limit risk for neurological disease. Interestingly, aging and neurodegeneration pose similar challenges to the brain’s immune environment, including aberrant inflammation and elevated exposure to lipid-rich debris from dying cells. The role of microglia, the brain’s innate immune cells, in responding to aging-associated damage has emerged as a promising avenue for investigation, galvanized by the identification of many myeloid-enriched genes associated with Alzheimer’s risk in a series of GWAS over the past decade. While specific states adopted by microglia may initially limit pathology to surrounding brain tissue, chronic challenges and exposure to debris may ultimately lead to maladaptive responses that can manifest as phagocytic ineptitude, production of inflammatory cytokines, and increased stress responses. Thus, identifying processes that rejuvenate responses of these cells to aging-associated challenges may provide a path for novel therapies limiting the impact of aging on neurological disorders. Modulating the systemic environment has emerged as one promising strategy to counteract age-related decline in cellular function. Exposure to factors present within young blood rejuvenates the aged brain, leading to increased synaptic plasticity and dendritic spine integrity, enhanced vascular remodeling, and improved learning and memory performance in aged mice. While much of this work has focused on the impact of blood-borne factors directly on neurons or adult neuroblasts in the hippocampus, recent work has suggested that microglia can take up proteins originating in plasma, suggesting that they may be responsive to blood-borne factors. Moreover, in response to treatment with plasma or a platelet factor acting on immune cells in the periphery, microglia appear to exhibit altered phagocytosis and activation state, respectively. Despite these findings, the field lacks a detailed characterization of how specific youth-associated factors affect microglial function and how such factors can be harnessed to revitalize the aged brain. We previously identified tissue inhibitor of metalloproteinases 2 (TIMP2) as a youth-associated blood-borne factor capable of revitalizing hippocampal function in aged mice. Levels of TIMP2 are elevated in very young human and mouse plasma and rapidly decline into adulthood and old age. Interestingly, a recent study finds that those expressing variants associated with higher plasma protein levels exhibit higher cognitive performance in a cohort of aged individuals at risk for developing AD. Aged mice treated systemically with TIMP2 exhibit improvements resembling those seen in mice treated with young plasma, including increased hippocampal plasticity and improved memory, likely as a result of direct TIMP2 action on CNS cells, given its entry from blood into brain. While TIMP2 has many canonical and non-canonical targets, these studies suggest that TIMP2 has myriad roles within the hippocampal microenvironment, yet its role in modulating innate immune function is understudied. We recently reported that TIMP2 plays a critical role in the young hippocampus in regulating memory, synaptic integrity, and adult neurogenesis through modulation of ECM homeostasis, processes that have been found to be regulated by microglia. Given the modulation by TIMP2 in processes linked to microglia function and the rejuvenating capacity of TIMP2 in aging contexts, we sought to determine how TIMP2 affects basic microglial function and whether systemic supplementation can restore protective microglial activities that are lost in the setting of age-related insults.