"Through studying a mouse model of Alzheimer's, the research team found that a series of genes related to mitochondrial metabolism in brain cells were more active than in normal mice," Reddy said. "Mitochondria are structures located in the cytoplasm of cells that produce energy for the cell. Prior research has linked Alzheimer's to mitochondrial function. However this is the first time genes that are responsible for early cellular change in Alzheimer's disease pathogenesis have been identified."
Currently, there are no early detectable biomarkers for Alzheimer's, and there is a lack of understanding of the functional changes caused by this disease, particularly at its early stages. To intervene before neurons become irreversibly damaged, an understanding of early cellular events in the progression of Alzheimer's is critical. Studies of "pre-symptomatic" human subjects suggest that pathologic changes in the brain occur years before symptoms are evident, suggesting that the brain tissue from patients dying from Alzheimer's exhibits physiologic features indicative of a very late stage in the degenerative process.
To determine early cellular changes connected to Alzheimer's disease, the OHSU scientists studied mice that overexpress human mutated amyloid precursor protein. These genetically-altered mice produce heightened levels of amyloid precursor protein. Over time, higher than normal levels of this protein can result in structures in the brain called beta amyloid plaques, which are thought to be either a cause or an effect of Alzheimer's disease.
By studying 11,283 mouse genes and using a gene chip technology called microarray, OHSU scientists were able to identify a much smaller set of distinct genes that functioned differently in the diseased mice from those in healthy mice. These genes are involved in mitochondrial energy metabolism and programmed cell death.
"We studied gene expression levels at three distinct stages of disease progression in the genetically-altered mice relative to age-matched wild-type normal mice," explained Reddy. "We conducted gene expression analysis long before (2 months of age), immediately before (5 months) and after (18 months) the appearance of beta amyloid plaques. In doing this, we found that these mitochondrial genes were more active at 2 months of age when compared to normal mice, and in some cases their activity heightened as the disease progressed. We believe the abnormal gene expression comes in response to beta amyloid-induced mitochondrial dysfunction, even in its early stages. Based on prior research, it's thought that energy metabolism in mitochondria is impaired by heightened levels of beta amyloid in the brain. We believe the genes identified in our study increase their activity to compensate for this damage, but unfortunately in the end they cannot keep up with the progression of Alzheimer's."
A companion study recently published in the journal NeuroMolecular Medicine also found very similar gene expression differences in Alzheimer's disease patients. Scientists believe this demonstrates the value of the mouse model in gaining new knowledge and developing future human therapies.
"This work likely will sharpen the focus of research on the possible links between mitochondrial gene expression and damage that occurs within and to neurons as Alzheimer's progresses. Understanding these links could lead to the development of novel and effective interventions for this disease," said Stephen Snyder, Ph.D., of the National Institute on Aging's (NIA) Neuroscience and Neuropsychology of Aging Program. The research was partially funded by the NIA, a component of the National Institutes of Health.
Additional financial support was provided by the Alzheimer's Association of Oregon, the Medical Research Foundation of Oregon, the American Federation for Aging Research, the Layton Aging and Alzheimer's Disease Center at OHSU, and an Advanced Research Career Development Award provided by the Department of Veterans Affairs.