Quantitative Changes in the Mitochondrial Proteome from Subjects with Mild Cognitive Impairment, Early Stage, and Late Stage Alzheimer's Disease

Issue title: Similarities and Differences Between Mild Cognitive Impairment and Alzheimer's Disease

Guest editors: Mark A. Lovell

Article type: Research Article

Authors: Lynn, Bert C.^{a; b; c; *} | Wang, Jianquan^a | Markesbery, William R.^{b; d} | Lovell, Mark A.^{a; b}

Affiliations: [a] Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA | [b] Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA | [c] University of Kentucky Mass Spectrometry Facility, University of Kentucky, Lexington, Kentucky, USA | [d] Departments of Neurology and Pathology, University of Kentucky, Lexington, Kentucky, USA | Sanders-Brown Center on Aging and Alzheimer's Disease Center, Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA

Correspondence: [*] Correspondence to: Bert C. Lynn, A053 ASTeCC Building, Lexington, KY 40506, USA. Tel.: +1 859 218 6529; Fax: +1 859 257 2489; E-mail: [email protected].

Abstract: The major barrier to treating or preventing Alzheimer's disease (AD) is its unknown etiology and pathogenesis. Although increasing evidence supports a role for mitochondrial dysfunction in the pathogenesis of AD, there have been few studies that simultaneously evaluate changes in multiple mitochondrial proteins. To evaluate changes in sites of potentially interacting mitochondrial proteins, we applied 2-dimensional liquid chromatography coupled with tandem mass spectrometry and the isotope coded affinity tag method to identify and quantify proteins in mitochondrial enriched fractions isolated from short postmortem interval temporal pole specimens from subjects with mild cognitive impairment (4 subjects pooled), early AD (4 subjects pooled), late-stage AD (8 subjects pooled) and age-matched normal control (7 subjects pooled) subjects. A total of 112 unique, non-redundant proteins were identified and quantified in common to all three stages of disease progression. Overall, patterns of protein change suggest activation of mitochondrial pathways that include proteins responsible for transport and utilization of ATP. These proteins include adenine nucleotide translocase, voltage dependent anion channels, hexokinase, and creatine kinase. Comparison of protein changes throughout the progression of AD suggests the most pronounced changes occur in early AD mitochondria.

Keywords: Disease progression, early Alzheimer's disease (EAD), isotope coded affinity tag (ICAT), LC/MS/MS, late Alzheimer's disease (LAD), mild cognitive impairment (MCI), mitochondria, proteomics, quantitative

DOI: 10.3233/JAD-2010-1254

Journal: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 325-339, 2010