Retromer Chaperone R33 Selectively Promotes Aβ Degradation by Microglia

Accumulation of abnormal amyloid and tau proteins in the brains is believed to be detrimental for brain functions; thus, searching for ways to reduce these bad proteins from the brain may help us find a promising drug for AD. We have found that a small chemical molecule can make microglia, a special brain cell with capability to clean up these bad proteins, and also help microglial cells to work more efficiently in clearance of amyloid proteins. This project will produce important information for us to understand how this small chemical helps microglia clean up amyloid proteins.

Microglia, the innate immune cells in brain, play important roles in clearance of neuro-toxic amyloid peptides from the brain, such as amyloid beta 42 (Aβ42).  The microglial cells internalize and deliver amyloid peptides to lysosomes, compartments within cells where proteins are sent for destruction (degradation) via a cellular process involving receptor sorting, which is controlled by the retromer complex. Using various molecular and cellular approaches, we are studying whether and how R33, a small molecule that stabilizes the retromer complex, promotes Aβ42 internalization and degradation by microglia. By addressing these questions, we shall provide valuable information for evaluating the therapeutic potential of R33, a retromer chaperone, in treating Alzheimer’s disease (AD).