Researchers at Oregon Health & Science University's Neurological Sciences Institute (NSI) have located a possible target for future therapies aimed at delaying or stopping Alzheimer's disease. Specifically, the therapy would target a structure in brain cells previously identified as being heavily involved in the degenerative disease. The research was led by P. Hemachandra Reddy, Ph.D., NSI scientist and senior author of the study. The results are published in the May 1 issue of the journal Human Molecular Genetics.
"This latest research more clearly demonstrates how structures, called mitochondria, in brain cells are a key part of the disease process in Alzheimer's. In fact, mitochondria appear to be a site where significant disease progression takes place," explained Reddy. "Research published by our lab in 2004 highlighted genes tied to this process. We also believe that toxins produced by the mitochondria contribute to Alzheimer's disease progression. In other words, the entire system may be one big feedback loop. Therefore, it is possible that therapies which encourage normal mitochondrial function may in fact delay or stop the disease in its early stages by breaking the loop."
To conduct the research, Reddy and his colleagues studied mice that are bred to have an Alzheimer's-like neurodegenerative disease. Like human Alzheimer's patients, the brains of these mice produce elevated levels of amyloid precursor protein (APP). They also develop formations called beta amyloid plaques. By observing mitochondrial function in brain cells of these mice, Reddy and his colleagues determined that beta amyloid could be found both inside and outside of the mitochondria. Because mitochondrial oxidative damage is a hallmark of Alzheimer's, the scientists believe the higher accumulations of these substances may be responsible. In addition, the scientists found increased levels of hydrogen peroxide in the Alzheimer's mice, likely produced by the mitochondria due to the oxidative damage.
"We believe that the disease produces mutant APP and beta amyloid which in turn impacts mitochondrial function. This results in increased production of hydrogen peroxide, resulting in a progression of the disease and higher levels of beta amyloid," said Reddy. "In other words - this model appears to be a vicious cycle where damage to brain cells increases and in fact feeds upon itself."
Previous and concurrent research in human tissue taken from Alzheimer's patients also confirmed increased levels of beta amyloid in brain cell mitochondria and appear to agree with these conclusions.
"The findings are very significant in providing a greater understanding the mechanisms behind Alzheimer's," explained study co-author Joseph F. Quinn, M.D., a clinical neurologist at the Layton Center for Aging & Alzheimer's Disease Research at OHSU and an associate professor of neurology, and cell and developmental biology in the OHSU School of Medicine. "In fact, OHSU is involved in a study funded by the National Institute on Aging of antioxidant therapy for Alzheimer's including antioxidants directed at the mitochondria."
While the human studies are launched, Reddy and his colleagues will continue complimentary studies in the mouse models for Alzheimer's to determine whether the oxidative damage to mitochondria can be prevented in early stages of disease progression.
The current research was funded by the American Federation for Aging Research, the Alzheimer's Disease Center of Oregon and the National Institutes of Health.
Study co-authors are: Maria Manczak (lead author), Thimmappa S Anekonda, OHSU Neurological Sciences Institute; Edward Henson and Joseph Quinn, Department of Neurology, OHSU School of Medicine; Byung S. Park, Division of Biostatistics, Department of Public Health and Preventive Medicine, OHSU School of Medicine.
OHSU's Neurological Science Institute is located on the university's West Campus in Beaverton. The NSI's mission is to advance our understanding of the brain and neurological disorders. NSI scientists use integrated and interdisciplinary approaches to expand knowledge about how the brain and nervous system function. Their goal is to translate new knowledge into innovative ways to diagnose, treat, cure and prevent neurological diseases and disorders.