Project Summary Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder associated with chronic neuroinflammation and the build-up of amyloid plaques and neurofibrillary tangles in the brain. A therapeutic approach that harnesses neuroinflammation and restores neuronal integrity can potentially be an effective means to alleviate the progression of neurodegeneration in AD. Here we provide novel findings supporting the notion that MG53, a tissue repair protein, can potentially slow AD neurodegeneration by protecting neurons from stress-induced injuries and mitigating neuroinflammation associated with AD. MG53 is a member of the TRIM protein family that plays an essential role in cell membrane repair. While predominantly expressed in skeletal muscle, moderate exercise can induce secretion of MG53 into circulation to elicit its tissue protective function. Transgenic mice with increased levels of MG53 in the bloodstream live a healthy lifespan and are resistant to stress-induced brain injury. Recombinant human MG53 (rhMG53) protein, administered systemically, can permeate the blood-brain barrier (BBB) to protect against traumatic brain injuries (TBI) in rodents and pigs. MG53 also passes through the BBB of human AD patients as it is detected in cerebrospinal fluid. In addition to facilitating tissue repair, MG53 has an anti-inflammation function that dampens neuroinflammation associated with TBI and LPS-neurotoxicity in mice. Pilot studies with AD mice reveal beneficial effects of rhMG53 to enhance neuronal integrity and reduce neuroinflammation through control of microglia activation. The long- term goal of this project is to decipher the physiology of MG53 in neuroprotection and to translate the basic findings into a clinical treatment for AD. We have assembled a team with complementary expertise in neurophysiology, microglia biology, innovative live-cell imaging, clinical AD research and unique animal models of AD, with the goal to arrive at a mechanistic understanding of MG53's dual function in control of neuroinflammation and in preservation of neuronal integrity during AD progression. The experiments designed in this proposal are focused on addressing the following three fundamental questions: How does MG53 contribute to the maintenance of neural integrity associated with the progression of AD? What are the mechanisms that underlie MG53's anti-inflammation function in the microglia? Can we target the dual function of MG53 as a means for alleviation of neurodegeneration associated with the progression of AD?