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 (A?) peptides and intraneuronal tangles of twisted tau protein fibers. Neuroinflammation is known to occur in AD, and when associated near A? 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 (A?) would have therapeutic immunomodulatory and localized disease-modifying activity at brain regions of A? accumulation and progressive neurodegeneration.
The aim of this proposal is to test the innovative concept that Tregs engineered to express CARs against A? 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 A? is present. The data generated will provide key proof-of-concept data to move this novel therapeutic idea forward
Recent advances in cell therapy with autologous effector T cells engineered to target and destroy tumor cells is leading to extraordinary breakthroughs in cancer treatment. The current proposal seeks to develop new technology for engineering regulatory T cells to have immunomodulatory activity and protect neurons from toxic inflammation in Alzheimer's Disease. Successful development of this innovative therapeutic strategy will be the foundation of new treatment approaches for patients.
