PROJECT SUMMARY AD is the most common cause of age-related dementia, and is characterized by a progressive impairment in cognitive function. Pathologically, AD patients exhibit Aβ plaques and neurofibrillary tangles with extensive neuronal and synaptic loss. Unfortunately, there is still no effective treatment for this devastating disease. Failures likely arise from amyloid accumulation 10-20 years prior to symptoms and the limited blood brain barrier (BBB) penetrance of many candidate therapies. Earlier diagnoses coupled with an effective and continuous source of in-brain therapy may therefore provide a powerful approach to ameliorate AD pathology. Herein we explore a transformative approach toward delivering therapeutic payloads into the brain to treat Aβ plaque load. We will test if engineered human microglia can be designed to safely and effectively deliver therapies into mouse models of AD. The first specific aim is to demonstrate the feasibility of the approach by determining the change in Aβ load with engineered microglia transplantation. The second aim will determine if reduced Aβ plaque load results in rescue of long-term potentiation defects. Overall, this R21 is poised to test the feasibility of novel and transformative approaches for safe and effective delivery of therapies to combat Aβ plaque buildup on AD. Successful demonstration of this approach could have far-reaching implications for the delivery of therapeutics into the brain.