Regulation of microglial function by blood-borne factors

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Project Summary: Age-related disorders such as Alzheimer’s disease (AD) present urgent issues to the aging population. Given the lack of universally effective treatments, novel approaches must be developed to reduce the impact of aging, the greatest risk factor for development of AD. Recent work has shown rejuvenation of age- sensitive organs, including the brain, through exposure to young blood. Our lab identified a loss of tissue inhibitor of metalloproteinase 2 (TIMP2) expression with age, and its restoration is critical in mediating the rejuvenating effects of young blood in aged animals. Despite these findings, the precise mechanism and cellular targets of TIMP2 have yet to be identified. It is currently unknown whether the positive effects of TIMP2 in aging generalize to the context of AD pathology. However, aging and AD present similar environmental challenges to the brain (e.g., inflammation, cellular debris from dying cells, toxic proteins). Based on the role of microglia in rapidly responding to debris (e.g., dying cells, amyloid, etc), we hypothesize that TIMP2 modulates microglial function. Consistent with this hypothesis, we have found that treatment with TIMP2 reduces microglial activation in the aged brain. Upon exposure to the debris of aging and AD, a subset of microglia acquires a disease- associated microglia (DAM) phenotype to respond to these challenges. This phenotype is initially protective by allowing microglia to effectively respond to environmental challenges, but unbridled activation can cause dysfunction or senescence of microglia and damage to surrounding tissue. Restoration of an effective response to debris may be critical to limit pathology. TIMP2 has been found to be a marker of the DAM transcriptional profile, and our preliminary data indicate that cell-intrinsic TIMP2 can regulate microglial state. This proposal aims to characterize microglial response to TIMP2 treatment and the cell-intrinsic role of microglial TIMP2 in enabling an effective response to debris in differing pathological contexts. Aim 1 will assess the morphological and inflammatory responses of microglia following treatment with TIMP2 in aged and AD pathological contexts to determine how microglia respond to damage following treatment. Furthermore, we will examine microglial- neuronal interactions in hippocampus using super-resolution microscopy and RNAscope. To probe the cell- intrinsic role of microglial TIMP2, Aim 2 will test the hypothesis that microglial TIMP2 rejuvenates response to aging and AD-associated pathology. We developed a mouse model that allows us to conditionally delete TIMP2 within microglia in diverse contexts. Upon deletion, we will examine response to debris by analyzing changes in pathology, morphology, cytokine release, and microglia-neuron interactions. The innovative methods employed in this proposal will provide insights into the role of TIMP2 acting as an extracellular protein on the function of microglia, while also probing cell-intrinsic effects of its activity in the context of debris associated with aging and AD. Characterization of the neuroimmune response to debris in different pathological conditions may facilitate development of therapies that slow down the aging process to limit onset of neurodegenerative diseases.