Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by impairment in memory, complex cognition, language, and visual or spatial skills. The exact cause for Alzheimer?s is poorly understood and currently there is no cure. One of the major disease hallmarks of Alzheimer?s is the buildup of harmful amyloid beta protein aggregates in the Alzheimer?s brain. Amyloid betas are normally removed by specialized cells in the brain called microglia. However, the removal of these aggregates leads to activation of the inflammatory pathway that eventually results to death of the brain cells. Using genetic engineering, we have created a new type of ?molecular bridge?, a hybrid protein that is designed to capture amyloid beta on one end and to bind to microglial MerTK receptor on the other end. The MerTK receptor activates a non-inflammatory phagocytic pathway which would have the advantage of clearing amyloid beta without eliciting the production of deleterious factors. If successful, this work could have a significant impact on the treatment for Alzheimer?s and likely other neurodegenerative disorders. Our long-term goal is to develop a novel therapeutic strategy for clearing deleterious metabolic products to prevent Alzheimer?s disease. Our immediate objective is to divert the clearance of amyloid beta from the inflammatory pathway to the non-inflammatory phagocytosis pathway. We have engineered hybrid proteins that can sequester and direct the clearance of both oligomeric and fibrillar forms of amyloid beta.
In Aim 1, we will characterize the Hybrid for MerTK dependency, specificity, immunogenicity, stability, and binding kinetics.
In Aim 2, we will test whether the Hybrid can prevent progression of AD in APP/PS1 and 3XTg mouse models.
In Aim 3, we will determine the molecular mechanism of Hybrid-mediated clearance of amyloid beta.
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