P4-145: Proteomics of mitochondria in Alzheimer’s disease brain

Abstract

Most cellular energy in the form of ATP is produced by mitochondria. Mitochondria also produce free radicals which can damage cellular structures. There is increasing evidence that mitochondrial dysfunction plays an important role in the pathology of a number of neurodegenerative diseases, including Alzheimer's disease (AD). Dysfunction of mitochondrial energy metabolism would lead to reduced ATP production and increased production of free radicals. Our hypothesis is that the proteins of the mitochondrial energy production system are reduced or oxidatively damaged in AD brains. To test this hypothesis, we are using a quantitative proteomics approach to compare the levels of the mitochondrial proteins in AD versus normal brain during the course of the disease. We are examining this issue using genetically altered triple transgenic mice (3xTg–AD; APPSwe, PS1M146V, tauP301L) which develop age–dependent accumulation of both amyloid plaques and neurofibrillary tangles, as well as age–associated memory impairments. Quantitative proteomics will be achieved using isotope–coded affinity tags (cICAT), followed by liquid chromatography and tandem mass spectrometry analysis (LC–MS/MS). Quantitative proteomics of mitochondrial proteins will be carried out using mitochondria isolated from the cortex and hippocampus of wild–type and 3xTg–AD mice at three stages of AD progression: before (2 months old); during (6 months of age); and after (15 months old) the appearance of amyloidal and tangle pathology and cognitive impairment. The findings from these studies should help further define the role of mitochondrial energy dysfunction in the pathogenesis of AD.