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UT Researcher Makes Strides in Alzheimer’s Research

Dr. Xuemin Xu and his team of researchers at the University of Tennessee College of Veterinary Medicine have made a discovery that could provide new information and lead to the development of methods of diagnosis and treatment of Alzheimer’s disease. Details of their research appear in the December 3 issue of Journal of Biological Chemistry. The paper has been selected as the journal’s “Paper of the Week” due to its significance and overall importance. According to the journal, its editorial board and associate editors select papers that rank in the top 1% of the 6,600 papers published each year to be “Paper of the Week”.

Alzheimer’s disease is the fourth leading cause of death in the United States. Deposition of amyloid beta-peptides in the brain is one of the characteristic features of the disease, and studies also strongly support the idea that the production and deposition of amyloid beta-peptide in the brain could be a causative event in Alzheimer’s disease. Xu and his team have discovered a new longer species of amyloid beta-peptide. Given the fact that studies suggest that the longer amyloid beta-peptides are more pathogenic than the shorter ones, the discovery of the new longer amyloid beta-peptide may provide a new therapeutic target for the development of methods of diagnosis and treatment of the disease.

Amyloid beta-peptide is produced from a large precursor protein by a sequence of steps or cleavage. Developing or identifying compounds (or so called inhibitors), which inhibit or reduce the production of amyloid beta-peptide is believed to be one of the more promising ways of prevention and treatment of the disease. To date, more than one dozen such inhibitors have been developed or identified. However, now Dr. Xu and his colleagues discovered that some of these inhibitors, which were previously known to inhibit the formation of secreted amyloid beta-peptides, now were found to cause an intracellular accumulation of an even longer amyloid beta-peptide species, which may have a deleterious effect. “These novel findings provide information important for the strategy of prevention and treatment of Alzheimer’s disease, aimed at the design of inhibitors,” concludes Dr. Xu.

Xu and his colleagues also discovered that the longer amyloid beta-peptide is produced by cleaving the precursor protein at a site previously unknown. Interestingly, the new cleavage site discovered by Dr. Xu’s group is the site of a mutation found in early-onset Alzheimer’s disease. This finding may open new avenues for investigating how this disease-linked mutation causes abnormal production of amyloid beta-peptide.

Xu, who has been conducting Alzheimer’s research for more than five years, says since Alzheimer’s is a disease associated with age and as people’s life spans are increasing, research on the disease is crucial. “This discovery will certainly provide important information for drug development and will also contribute to our knowledge about the cause of the disease.”

Xu’s research is funded by a million dollar grant from the National Institute of Neurological Disorders and Stroke. Other members of the research team are Guojun Zhao, Guozhang Mao, Jianxin Tan, Yunzhou Dong, Jeff L. Wiles, and Mei-Zhen Cui.

Sandra Harbison
Media Relations
UT College of Veterinary Medicine

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