Project Summary/Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease that is one of the primary reasons for memory dysfunction and dementia after 60 years of age. Neuronal dysfunction and death in the frontal cortex and hippocampus, along with microglia-mediated neuroinflammation and formation of aberrant protein aggregates and fibrils are hallmarks of AD. Sporadic and familial forms of AD have an overproduction and/or decreased clearance of extracellular amyloid-beta (Aβ) peptides and intraneuronal tangles of twisted tau protein fibers. Neuroinflammation is known to occur in AD, and when associated near Aβ plaques there is a greater neurodegeneration. Data suggest that inflammatory microglia, the resident macrophages of the central nervous system, have a role in neurodegeneration and cognitive decline. T regulatory cells (Tregs) are a subset of T cells that have inherent anti-inflammatory and immunomodulatory properties. Tregs are found in the CNS under steady state conditions and increase trafficking to regions of CNS inflammation. Less active or decreased numbers of Tregs has been found in AD patients and depletion of Tregs can accelerate cognitive defects in murine AD models. We hypothesize that Tregs expressing chimeric antigen receptors (CARs) with specificity to amyloid-beta (Aβ) would have therapeutic immunomodulatory and localized disease-modifying activity at brain regions of Aβ accumulation and progressive neurodegeneration. The aim of this proposal is to test the innovative concept that Tregs engineered to express CARs against Aβ will demonstrate immunoregulatory and neuroprotective activities in mouse models of Alzheimer's disease. We will test murine and human Tregs for activity in AD models when Aβ is present. The data generated will provide key proof-of-concept data to move this novel therapeutic idea forward