Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder marked by accumulation of extracellular amyloid beta (A?) and intracellular neurofibrillary tau tangles. It is the most common form of dementia, the fifth leading cause of death, and a huge societal and economic burden. Disease-modifying drugs are still limited. Clinical trials for AD focus on clearing A?, the disease-causing agent according to the "amyloid cascade hypothesis". However, these therapies do not consider the downstream contribution of microglia, the immune cells of the brain. Microglia are key players in the "cellular phase theory", which claims that while A? functions as an initial trigger, it is the multitude of cellular changes that lead to disease. I will combine both theories in a new paradigm inspired by one of the most promising treatments in cancer, CAR-T cells, and develop a CAR-microglia system for AD. I will perform a CRISPR-Cas KO screen coupled with an A? phagocytosis assay to study the interactome between A? and human microglia. Hits that lead to altered A? phagocytosis will be used to engineer CAR-microglia cells with high affinity for A?. I will test the efficiency of these cells in clearing A? in vivo using a humanized AD mouse model. Finally, I will provide target engagement readouts of the most promising CAR-microglia with amyloid-PET imaging and CSF analysis. This project will provide new insights on the A?-microglia interactome and deliver an entirely new therapeutic approach for AD.
Researcher(s)
Research team(s)
Project type(s)