The search for genetic and environmental factors that may interact with the processes of advancing age to increase the incidence of Alzheimer's disease (AD) is an ongoing effort in many laboratories. Most of the efforts in discovering genetic factors associated with AD are centered on the nuclear genome. Yet, many studies have shown that mitochondrial structure and function change with both advancing age and, especially, with the onset and progression of AD. Investigators at the University of Kansas (KU) have been investigating the effects of cardiorespiratory fitness on AD progression and on the genetic and biochemical changes in brain mitochondria during the aging process and in AD. This combination of expertise and interests has led us to this proposed Core G, the Mitochondrial Genomics and Metabolism (MGM) Core. The goal of the MGM Core is to provide resources and expertise to investigators at KU and at other research institutions that will support studies on platelet, brain and muscle mitochondria obtained from well-characterized cases of AD, mild cognitive impairment (MCI), and age-matched controls. The scientific focus of the MGM Core is based on the idea that mitochondria play an important role in the pathogenesis of AD, both familial and late onset AD. The generation of reactive oxygen species in mitochondria, especially mitochondria with defective metabolism such as those in AD, can lead to oxidative modification of mtDNA, increases in the frequency of mutations in mtDNA, and mitochondrial dysfunction in terms of oxidative phosphorylation The Specific Aims of the MGM Core are: 1) Prepare, catalog, and store mitochondria, protein extracts, DNA, and RNA from living and deceased subjects recruited by the Clinical Core;2) Prepare and bank cybrid lines using neuronal cells and platelet mitochondria from living subjects;3) Perform limited mitochondrial DNA (mtDNA) sequence analysis and measurements of 8-OH-2-dG in order to jump-start larger, independently funded research into AD mtDNA gene structure and expression;and 4) Develop mitochondria- and metabolism-oriented AD research in the Kansas City region and assist in national AD research efforts focused on mitochondria.
The genetic factors that lead to the Alzheimer's disease state are still not fully defined. Mitochondrial abnormalities in structure and function may be a common mechanism underlying the appearance and progression of AD. Investigation of mitochondrial function is one of the main avenues of future research that will be conducted by investigators at the University of Kansas and other institutions.
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