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.
Robert Marr, working under Inder Verma at the Salk Institute in collaboration with the laboratories of Fred H. Gage at the Salk Institute and Eliezer Masliah at UCSD, 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.
"This study supports a role for neprilysin in the regulation of beta-amyloid," said Verma, a Salk professor who is internationally recognized for his research on gene therapy. "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, a Salk professor who has made important contributions to our understanding of Alzheimer's disease during the past decade. "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 at the Salk Institute and other institutions 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.
The group is currently conducting mouse experiments to determine if neprilysin gene therapy results in any cognitive improvements in the mice. They are also investigating how the therapy works at different stages of the disease.
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.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.