Quantitative proteomic analysis of mitochondria in aging PS-1 transgenic mice

You Jun Fu, Shuling Xiong, Mark A. Lovell, Bert C. Lynn

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Accumulating evidence suggests mitochondrial alterations are intimately associated with the pathogenesis of Alzheimer's disease (AD). In order to determine if mutations of presenilin-1 (PS-1) affect levels of mitochondrial proteins at different ages we enriched mitochondrial fractions from 3-, 6-, 12-month-old knock-in mice expressing the M146V PS-1 mutation and identified, and quantified proteins using cleavable isotope-coded affinity tag labeling and two-dimensional liquid chromatography/tandem mass spectrometry (2D-LC/MS/MS). Using this approach, 165 non-redundant proteins were identified with 80 of them present in all three age groups. Specifically, at young ages (3 and 6 months), Na+/K+ ATPase and several signal transduction proteins exhibited elevated levels, but dropped dramatically at 12 months. In contrast, components of the oxidative phosporylation pathway (OXPHOS), the mitochondrial permeability transition pore (MPTP), and energy metabolism proteins remained unchanged at 3 months but significantly increased with age. We propose that alterations in calcium homeostasis induced by the PS-1 mutation have a major impact in young animals by inhibiting the function of relevant proteins and inducing compensatory changes. However, in older mice combination of the PS-1 mutation and accumulated oxidative damage results in a functional suppression of OXPHOS and MPTP proteins requiring a compensatory increase in expression levels. In contrast, signal transduction proteins showed decreased levels due to a break down in the compensatory mechanisms. The dysfunction of Na +/K+ ATPase and signal transduction proteins may induce impaired cognition and memory before neurodegeneration occurs.

Original languageEnglish
Pages (from-to)649-664
Number of pages16
JournalCellular and Molecular Neurobiology
Issue number5
StatePublished - Jul 2009

Bibliographical note

Funding Information:
Acknowledgment This study was supported by National Institute of Health grant (NIH/NIA Grant # 1R01 AG25403-04). Our bioinformaics resources were supported by NCRR(NIH) Grant P 20 RR16481. The authors thank the University of Kentucky Mass Spectrometry Facility (http://www.rgs.uky.edu/ukmsf) for laboratory resources.


  • Alzheimer's disease
  • LC/MS/MS
  • Mitochondria
  • Presenilin mutation
  • Proteomics

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology


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