Approximately 5 million Americans over age 60 suffer from Alzheimer’s disease (AD), and this number is projected to surpass 13 million by 2050. In the U.S., the cost of care was estimated at $259 billion in 2017, making this a huge public health concern and an enormous financial burden. Repetitive traumatic brain injuries (TBIs) significantly increase the risk of developing neurodegeneration, most notably Chronic Traumatic Encephalopathy (CTE), but also AD. The overlap between repetitive TBIs and AD suggests that therapeutic approaches demonstrating benefits in acute injuries may also have potential in treating AD. Astrocytes, the major support cell in the brain, are fundamental to central nervous system (CNS) integrity through regulation of processes including synaptic transmission, metabolite transport, blood-brain-barrier integrity, and inflammatory astrogliosis. Astroglial pathology is prominent in both AD and CTE and represents a critical knowledge gap and potential therapeutic opportunity. Astrocyte Pharmaceuticals has demonstrated that the intrinsic healing mechanisms of astrocytes could be stimulated by certain small molecule purinergic agonists. These agonists increase mitochondrial ATP production and drive an energy-dependent reduction in the size of neuronal lesions in preclinical models of brain injury. AST-004, a novel adenosine A1/A3 receptor agonist, demonstrates significant and diverse cerebroprotective efficacy in a broad range of acute brain injury models. In preliminary experiments, chronic AST-004 administration produced significant reductions in Aβ plaques in a mouse model of AD. Based on these promising results, the goals of this project are to 1) systematically characterize the cerebroprotective efficacy of chronic AST-004 treatment in AD mice using both molecular and behavioral measures, and 2) produce additional GMP AST-004 drug substance to support long-term oral GLP toxicology studies. A successful outcome of this study also has the potential to bring a desperately need AD therapy to millions of patients with AD and their caregivers.