March 25, 2003

Gene Transfer Reduces Levels of Key Alzheimer's Disease Protein

A molecule that naturally degrades a protein linked to Alzheimer's disease appears to reduce the levels of that protein by nearly 50 percent when delivered by gene therapy, researchers in the University of California, San Diego (UCSD) School of Medicine and the Salk Institute have found in collaboration with researchers at the University of Kentucky. The findings appear in the March 15, 2003 issue of the Journal of Neuroscience.  

The study indicates that gene therapy may provide an effective way to treat Alzheimer's by producing - in the body - a molecule that reduces naturally the accumulation of the protein beta-amyloid. Beta-amyloid constitutes the plaques seen in the brains of people who have died from the disease.

Eliezer Masliah, M.D., in his laboratory

Eliezer Masliah, M.D., UCSD professor of neuroscience and senior author of the paper, noted that "this is a significance advancement in that it provides a gene therapy approach for the treatment of Alzheimer's disease that not only reduces the accumulation of amyloid in the brain and the formation of plaques, but probably also degrades the more toxic smaller fragments of amyloid responsible for the toxic effects in the brain.

Robert Marr, working under Inder Verma at the Salk Institute in collaboration with Masliah and Fred H. Gage at the Salk Institute, used a modified version of the HIV virus to transfer a gene called neprilysin to neurons of transgenic mice producing human beta-amyloid, which lowered levels of the harmful protein to half that found in untreated animals.  Furthermore, treatment was shown to eliminate the degeneration that was caused by buildups of beta-amyloid. The study marks the first time researchers could directly show that neprilysin inhibits beta-amyloid accumulation in animals.

"These mice also show healthier and more complex synaptic contacts," Masliah said. "This is relevant in that it suggests that the memory and cognitive changes might be also reversed. We are currently investigating this possibility."

"This study supports a role for neprilysin in the regulation of beta-amyloid," said Verma. "It highlights the potential of using viral vectors for a gene therapy approach to treat, or perhaps prevent, Alzheimer's disease."

"What's significant about this is that neprilysin isn't a drug, but a molecule that controls levels of beta-amyloid naturally," said Gage. "This study is an example of how understanding the basic mechanisms of protein interaction can lead to new disease treatments."

Usually controlled by neprilysin, beta-amyloid exists in normal brains at far lower levels than seen in Alzheimer's disease. Its role in brain function is still in question, but scientists suspect it plays important roles in transporting sub-cellular structures and molecules from one end of a nerve cell to another.

Alzheimer's disease is the most common form of dementia among older people. An estimated four million Americans suffer from the disease, which is marked by a progressive, severe loss of memory and ability to reason. Eventually, the disease progresses to the point that patients need 24-hour care. The disease' cause is unknown, but autopsy results clearly point to the accumulation of beta amyloid plaques and other abnormal structures called tangles in brain tissue.

Co-authors of this work also include Edward Rockenstein, UCSD, Mark Kindy, University of Kentucky, and Atish Mukherjee working under Louis Hersh, University of Kentucky.  The team's research is supported by a $5 million, five-year grant from the National Institute on Aging.  Robert Marr is supported by funds from the Canadian Institutes of Health Research.

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