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 glia-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. Furthermore, peripheral immune activity and inflammation can affect inflammation in the CNS. 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) will have immunomodulatory activity and improve cognitive function of the 5xFAD B6 mice, a murine AD model. The aim of this proposal is to test the innovative concept that Tregs engineered to express CARs against amyloid-beta will demonstrate immunomodulatory effects in the CNS and in the peripheral tissues resulting in improved cognitive behavior. The data generated will provide key proof-of-concept data to develop this novel therapeutic idea forward.