Summary of R01 Parent Grant, R01AG061382. Aging is the major risk factor for dementias such as Alzheimer’s disease. Novel targets and strategies are needed as the number of adults over the age of 65 in the United States is expected to reach 80 million by the year 2040. Though the conventional view holds that plasticity is limited in the aged brain, emerging data have challenged this notion, revealing that factors present within young blood are restorative for aged tissues throughout the body while suggesting links between the systemic environment and aging and Alzheimer’s disease-related changes in the brain. Aged mice sharing young blood via the parabiosis model or through plasma transfer exhibit improved synaptic plasticity, dendritic spine number, and cognitive performance, which led us to explore novel brain activities for systemic protein factors that may have relevance for Alzheimer’s disease. Our recently published work uncovered that tissue inhibitor of metalloproteinases 2 (TIMP2), a protein enriched in developmentally early human and young mouse plasma versus aged plasma, plays a surprising central role in regulating synaptic plasticity within the hippocampus (Castellano et al., 2017, Nature). We showed that treatment with TIMP2 significantly revitalizes hippocampal function as assessed by gene expression, long-term potentiation, and memory performance in hippocampal-dependent behavioral tasks. Moreover, removing TIMP2 from hippocampal slices dramatically reduced LTP and its loss in plasma ablated cognitive improvements conferred by young plasma. This work has nonetheless left open many fundamental questions related to TIMP2's function within the hippocampus, and its role in AD remains unexplored. Recent work shows significantly reduced TIMP2 levels in Alzheimer’s disease patients with vascular changes in CSF and altered levels of TIMP2 target MMP2 in plasma; our preliminary data support a perturbation of TIMP2 metabolism in plasma in mouse models of Alzheimer’s disease pathology. We also find that TIMP2 expression decreases within dentate gyrus mossy cells important for the LTP response. In this work, we will probe the mechanism by which CNS TIMP2 directly regulates hippocampal function and the extent to which TIMP2 regulates hippocampal function in Alzheimer’s disease via changes in synaptic integrity as well as amyloid-β (Aβ)-dependent mechanisms. We hypothesize that TIMP2 regulates synaptic function in the normal hippocampus and is restorative in the context of Alzheimer’s disease pathology, primarily by acting to maintain synaptic integrity. We will address this hypothesis in three major aims: (1) To assess functional effects in mice in which hippocampal TIMP2 has been targeted and to evaluate the contribution of its source in mossy cells to plasticity, (2) to assess the role of canonical and putative TIMP2 targets within the hippocampus, (3) and to investigate the role of TIMP2 and related pathways in amyloid-independent and amylo...