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2015 Grants - Zhao
PICALM-Mediated Autophagic Aß Clearance and Toxicity Mitigation in Pericytes
Zhen Zhao, Ph.D.
University of Southern California
Los Angeles, California
2015 New Investigator Research Grant
Can variations in the PICALM gene promote the risk for Alzheimer’s disease by hindering the cells that help remove beta-amyloid from the brain?
The blood-brain barrier is a specialized structure that surrounds the brain and acts as a “filter” to prevent harmful blood-borne substances from entering the brain while allowing important nutrients to cross. One group of cells called pericytes support the blood brain barrier by helping to remove harmful cellular debris from the brain. In Alzheimer’s disease, however, pericytes appear to become damaged and lose their ability to carry out normal functions. Such damage may promote the brain accumulation of beta-amyloid and other toxic molecules linked to Alzheimer’s. It is not yet understood how pericytes contribute to the removal of beta-amyloid from the brain in Alzheimer’s disease.
Zhen Zhao, Ph.D., and colleagues have been studying the molecular mechanisms of how pericytes clear beta-amyloid from the brain. They found that this clearance involves a gene called PICALM, which codes for a protein known as phosphatidylinositol binding clathrin assembly protein. Other studies have found that certain variations of the PICALM gene are linked to an increased risk for Alzheimer’s disease. Taken together, these findings suggest that PICALM dysfunction plays an important role in Alzheimer’s — possibly by hindering pericytes from clearing toxic beta-amyloid and enabling the protein fragment to accumulate in the brain and damage nerve cells.
For their current grant, Dr. Zhao and colleagues will conduct further studies of pericyte function in brain cells grown in laboratory dishes and in mice engineered to develop Alzheimer’s-like brain changes. They plan to determine how alterations in PICALM impact the ability of pericytes to break down and clear beta-amyloid from the brain.
The results of these studies could shed new light on our understanding of how variations in the PICALM gene may increase the risk for Alzheimer’s disease. This work will also help clarify how pericytes clear material from the brain, and their role in beta-amyloid toxicity in Alzheimer’s disease. Ultimately, these findings could lead to the development of novel therapies for preventing Alzheimer’s or slowing its progression.