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Mol Brain. 2019 Jan 28;12(1):8. doi: 10.1186/s13041-019-0430-y.

Quantitative profiling brain proteomes revealed mitochondrial dysfunction in Alzheimer's disease.

Author information

1
School of Biological Sciences, Division of Structural Biology and Biochemistry, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore. ssadav@ntu.edu.sg.
2
Singapore Phenome Centre, Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Singapore. ssadav@ntu.edu.sg.
3
School of Biological Sciences, Division of Structural Biology and Biochemistry, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
4
School of Biological Sciences, Division of Structural Biology and Biochemistry, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore. sksze@ntu.edu.sg.

Abstract

Mitochondrial dysfunction is a key feature in both aging and neurodegenerative diseases including Alzheimer's disease (AD), but the molecular signature that distinguishes pathological changes in the AD from healthy aging in the brain mitochondria remain poorly understood. In order to unveil AD specific mitochondrial dysfunctions, this study adopted a discovery-driven approach with isobaric tag for relative and absolute quantitation (iTRAQ) and label-free quantitative proteomics, and profiled the mitochondrial proteomes in human brain tissues of healthy and AD individuals. LC-MS/MS-based iTRAQ quantitative proteomics approach revealed differentially altered mitochondriomes that distinguished the AD's pathophysiology-induced from aging-associated changes. Our results showed that dysregulated mitochondrial complexes including electron transport chain (ETC) and ATP-synthase are the potential driver for pathology of the AD. The iTRAQ results were cross-validated with independent label-free quantitative proteomics experiments to confirm that the subunit of electron transport chain complex I, particularly NDUFA4 and NDUFA9 were altered in AD patients, suggesting destabilization of the junction between membrane and matrix arms of mitochondrial complex I impacted the mitochondrial functions in the AD. iTRAQ quantitative proteomics of brain mitochondriomes revealed disparity in healthy aging and age-dependent AD.

KEYWORDS:

Alzheimer’s disease; Complex I; Mitochondrial dysfunction; Mitochondriome; Neurodegenerative diseases; Proteomics; iTRAQ

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