Early dysregulation of the mitochondrial proteome in a mouse model of Alzheimer's disease

• Published in: Journal of proteomics Vol. 74; no. 4; pp. 466 - 479
• Main Authors: Chou, Jose L., Shenoy, Deepa V., Thomas, Nicy, Choudhary, Pankaj K., LaFerla, Frank M., Goodman, Steven R., Breen, Gail A.M.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.04.2011; Elsevier
• Subjects: 2D-DIGE; Adult and adolescent clinical studies; Alzheimer disease; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; amyloid; animal models; Animals; apoptosis; Biological and medical sciences; BN/SDS-PAGE; Comparative proteomics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Disease Progression; Diverse techniques; fatty acids; Fundamental and applied biological sciences. Psychology; gel electrophoresis; gene expression regulation; genetically modified organisms; glycolysis; Humans; IEF/SDS-PAGE; Insulin-Like Growth Factor Binding Proteins - analysis; Insulin-Like Growth Factor Binding Proteins - chemistry; ion transport; Male; Medical sciences; mice; Mice - metabolism; Mice, Transgenic; mitochondria; Mitochondrial Proteins - analysis; Mitochondrial Proteins - metabolism; Mitochondrial proteomics; Models, Biological; Molecular and cellular biology; mutation; Neurofibrillary Tangles - metabolism; Neurology; Organic mental disorders. Neuropsychology; oxidation; oxidative phosphorylation; oxidative stress; pathogenesis; protein synthesis; proteome; Proteome - analysis; Proteome - metabolism; proteomics; Proteomics - methods; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; pyruvic acid; tandem mass spectrometry; Time Factors; transgenes; tricarboxylic acid cycle; Triple transgenic AD mice; Two-Dimensional Difference Gel Electrophoresis - methods; IEF/SDS-PAGE; 2D-DIGE; Mitochondrial proteomics; Comparative proteomics; BN/SDS-PAGE; Alzheimer's disease; Triple transgenic AD mice; Animal model; Alzheimer disease; Rodentia; Transgenic animal; Proteome; Vertebrata; Mitochondria; Mammalia; Mouse; Proteomics; Early
• ISSN: 1874-3919; 1876-7737
• DOI: 10.1016/j.jprot.2010.12.012

Mitochondrial structural and functional alterations appear to play to an important role in the pathogenesis of Alzheimer's disease (AD). In the present study, we used a quantitative comparative proteomic profiling approach to analyze changes in the mitochondrial proteome in AD. A triple transgenic mouse model of AD (3xTg-AD) which harbors mutations in three human transgenes, APP Swe, PS1 M146V and Tau P301L, was used in these experiments. Quantitative differences in the mitochondrial proteome between the cerebral cortices of 6-month-old male 3xTg-AD and non-transgenic mice were determined by using two-dimensional difference gel electrophoresis (2D-DIGE) and tandem mass spectrometry. We identified 23 different proteins whose expression levels differed significantly between triple transgenic and non-transgenic mitochondria. Both down-regulated and up-regulated mitochondrial proteins were observed in transgenic AD cortices. Proteins which were dysregulated in 3xTg-AD cortices functioned in a wide variety of metabolic pathways, including the citric acid cycle, oxidative phosphorylation, pyruvate metabolism, glycolysis, oxidative stress, fatty acid oxidation, ketone body metabolism, ion transport, apoptosis, and mitochondrial protein synthesis. These alterations in the mitochondrial proteome of the cerebral cortices of triple transgenic AD mice occurred before the development of significant amyloid plaque and neurofibrillary tangles, indicating that mitochondrial dysregulation is an early event in AD. [Display omitted]