Alzheimer's precursor protein controls its own fate

A research team led by the University of South Florida Department of Psychiatry & Behavioral Neurosciences has found that a fragment of the amyloid precursor protein (APP) - known as sAPP-α and associated with Alzheimer's disease - appears to regulate its own production. The finding may lead to ways to prevent or treat Alzheimer's disease by controlling the regulation of APP.

Their study is published online in Nature Communications.

"The purpose of this study was to help better understand why, in most cases of Alzheimer's disease, the processing of APP becomes deregulated, which leads to the formation of protein deposits and neuron loss," said study senior author Dr. Jun Tan, professor of psychiatry and the Robert A. Silver Chair, Rashid Laboratory for Developmental Neurobiology at the USF Silver Child Development Center. "The many risk factors for Alzheimer's disease can change the way APP is processed, and these changes appear to promote plaque formation and neuron loss."

An estimated 30 million people worldwide and 5 million in the U.S. have Alzheimer's. With the aging of the "Baby Boom" generation, the prevalence of the debilitating disease is expected to increase dramatically in the U.S. in the coming years. Currently, there are no disease-modifying treatments to prevent, reverse or halt the progression of Alzheimer's disease, only medications that may improve symptoms for a short time.

"For the first time, we have direct evidence that a secreted portion of APP itself, so called 'sAPP-α,' acts as an essential stop-gap mechanism," said the study's lead author Dr. Demian Obregon, a resident specializing in research in the Department of Psychiatry & Behavioral Neurosciences at USF Health. "Risk factors associated with Alzheimer's disease lead to a decline in sAPP-α levels, which results in excessive activity of a key enzyme in Aβ formation,"

In initial studies using cells, and in follow-up studies using mice genetically engineered to mimic Alzheimer's disease, the investigators found that the neutralization of sAPP-α leads to enhanced Aβ formation. This activity depended on sAPP-α's ability to associate with the APP-converting enzyme, BACE1. When this interaction was blocked, Aβ formation was restored.

The authors suggest that through monitoring and correcting low sAPP-α levels, or through enhancing its association with BACE, Alzheimer's disease may be prevented or treated.

Dr. Demian Obregon and Dr. Lucy Hou of the USF Department of Psychiatry and Behavioral Neurosciences, the study's lead authors, collaborated with colleagues from the Laboratory of Neurosciences at the National Institute on Aging and colleagues at the USF Center for Aging and Brain Repair, the James A. Haley Veterans' Hospital and Saitama Medical University in Japan. Other study authors included: Juan Deng, MD; Brian Giunta, MD; Jun Tian, BS; Donna Darlington, MS; Md Shahaduzzaman, MD; Yuyuan Zhu, MD, PhD; Takashi Mori, DVM, PhD; and Mark P. Mattson, PhD.

The research was supported by a grant from the National Institutes of Health, National Institute on Aging, and a Veterans Affairs Merit grant.

USF Health's mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician's Group. The University of South Florida is a global research university ranked 34th in federal research expenditures for public universities.

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