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Dr. Shi Du Yan: A Leading Investigator in Novel Therapeutic Approaches to Alzheimer's Disease

Shi Du Yan, MD

Alzheimer's disease (AD) is the most frequent cause of dementia in the elderly, afflicting as many as 4.5 million Americans. The neuronal stress and cell death associated with AD not only result in memory loss, as commonly known, but also impair thinking processes (cognition). Most people develop AD after age 60, and the risk level for the disease increases with age. Although no cure currently exists for Alzheimer's, new treatments are on the horizon as a result of accelerating insights into the biology of the disease. "Finding out why Alzheimer's occurs and what causes brain cells to die is vital to the development of therapies that might improve quality of life for the elderly," says Dr. Shi Du Yan, Professor of Clinical Pathology (in Surgery) at NewYork-Presbyterian Hospital/Columbia University Medical Center (NewYork-Presbyterian/Columbia).

Dr. Yan's research focuses on investigating potential causes of AD. The National Institutes of Aging has awarded a program project grant on mechanisms of cell stress and survival in neurodegenerative disorders to Dr. Yan, who is part of the Division of Surgical Science, and her collaborators in the Departments of Surgery, Pathology, Obstetrics & Gynecology, and Medicine. Their grant work focuses on the role of two molecular targets of amyloid-beta peptide(Aß). Investigations with genetically manipulated mice have suggested that this peptide may be the central agent causing neuronal dysfunction in Alzheimer's disease. Drs. Richard Mayeux and Michael L. Shelanski from the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at NewYork-Presbyterian/Columbia are key collaborators in this work.

"A neurotoxic peptide, amyloid-beta peptide is a principal component of amyloid plaque, which is the hallmark of Alzheimer's disease. Genetic, cell biology, biochemical, and animal studies all support the concept that Aß plays a central role in the development of Alzheimer's pathology. However, the mechanisms of Aß-induced neuronal toxicity have not yet been completely defined," explains Dr. Yan.

Dr. Yan and her research team are investigating two cellular targets of Aß for evidence of Aß-induced cellular stress:

• RAGE (Receptor for Advanced Glycation End products)
• ABAD (Amyloid Binding Alcohol Dehydrogenase)

"The goal of our studies is to gain insights into the role of these two inter-related cellular targets in order to ascertain their contributions to Aß-mediated neuronal damage relevant to Alzheimer's disease," says Dr. Yan. "We have found that interaction of RAGE and ABAD with amyloid-beta peptide causes accelerated spatial learning/memory deficits and synaptic dysfunction, and more prominent neuropathologic changes as evidenced by observations in double transgenic mice. All of our findings indicate that cell surface RAGE and intracellular ABAD service as cellular co-factors for promoting Aß-mediated neuronal toxicity relevant to Alzheimer's disease. In the future, we may blockade RAGE or ABAD as a novel therapeutic approach in the treatment of Alzheimer's disease."

Dr. Yan and her research team's findings have been published in Nature, Nature Medicine, Science, The EMBO Journal, and The FASEB Journal. Dr. Yan has authored 59 peer-reviewed articles, 23 book chapters and reviews, and 54 abstracts. In addition, she has garnered numerous honors and awards. She has been recognized for outstanding service by the Alzheimer's Association's Initial Review Board, and is the recipient of the Young Investigator Award from the National Institutes of Health (Aging Division).