Cellular Mechanisms Underlying Microglia-Mediated Amyloid Degradation

Wenjie Luo, PhD
Weill Cornell Medicine (New York, NY)
Year Awarded:
Grant Duration:
July 1, 2016 to June 30, 2019
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Northeastern
Wenjie Luo, PhD

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).

About the Researcher

Dr. Luo is an assistant professor at the Appel Alzheimer’s Disease Research Institute, a part of the Brain and Mind Research Institute of Weill Cornell Medical College. Her research focuses on studying how the brain’s innate immune cell, the microglia, function or fail to function in Alzheimer’s disease (AD). Her group recently discovered a role for microglia in the clearance of pathological tau proteins, the major component of neurofibrillary tangles in the AD brain. They are investigating the mechanisms by which microglia regulate the pathogenic accumulation of amyloid and tau during the progression of the disease. Dr. Luo has broad training in cell biology, genetics and biochemistry. She received her bachelor of science degree in cell biology and genetics from Peking University in China, and her PhD in cell biology and genetics from Albert Einstein College of Medicine in Bronx, NY. She finished her postdoctoral training at The Rockefeller University studying the molecular and cellular mechanisms of AD. Her previous work contributed to our in-depth understanding of intracellular trafficking of amyloid precursor protein and its cleaving enzyme, gamma-secretase, in AD. She also discovered a therapeutic role for small molecule inhibitors of heat shock protein 90 (Hsp90) in regulating tau degradation and aggregation using disease-relevant cell and animal models.

Personal Story

In conversations with older neighbors, I frequently run into people who are worried about their mental and cognitive health and are eager to know about any therapeutic breakthrough in Alzheimer’s disease (AD) treatment. It is tough for me to answer their questions by simply saying “not yet.” From their eyes, I deeply feel how important and urgent it is for us to push our research forward, to understand this deadly disease and to find new and effective treatments.

At dinnertime, one of our family’s most popular topics for discussion is AD. My kids are learning more and more about this disease through our daily chats. They have begun to use their knowledge about AD at school. My son recently created a school play about an AD patient and his family and how music helps the caregiver’s dad remember his children. My daughter, a high school sophomore, began coming to my lab to help in our research projects during holidays and weekends. Really inspired by how BrightFocus donors use their money to support research, my daughter donated part of her award from an art competition to BrightFocus Foundation. At that moment, I clearly saw the enormous impact that BrightFocus donors have on our next generation. I strongly believe that a combined effort of scientists and caring people like BrightFocus donors will fight and eventually cure this deadly disease.

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