Oxidative modification and down-regulation of Pin1 in Alzheimer's disease hippocampus: A redox proteomics analysis

Rukhsana Sultana, Debra Boyd-Kimball, H. Fai Poon, Jain Cai, William M. Pierce, Jon B. Klein, William R. Markesbery, Xiao Zhen Zhou, Kun Ping Lu, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

214 Scopus citations

Abstract

Alzheimer disease (AD) is characterized neuropathologically by intracellular neurofibrillary tangles (NFT) and of extracellular senile plaques (SP), the central core of which is amyloid beta-peptide (Aβ) derived from amyloid precursor protein (APP), a transmembrane protein. AD brain has been reported to be under oxidative stress that may play an important role in the pathogenesis and progression of AD. The present proteomics study is focused on identification of a specific target of protein oxidation in AD hippocampus that has relevance to the role of oxidative stress in AD. Here, we report that the protein, Pin1, is significantly down-regulated and oxidized in AD hippocampus. The identity of Pin1 was confirmed immunochemically. Analysis of Pin1 activity in AD brain and separately as oxidized pure Pin1 demonstrated that oxidation of Pin1 led to loss of activity. Pin1 has been implicated in multiple aspects of cell cycle regulation and dephosphorylation of tau protein as well as in AD. The in vivo oxidative modification of Pin1 as found by proteomics in AD hippocampus in the present study suggests that oxidative modification may be related to the known loss of Pin1 isomerase activity that could be crucial in AD neurofibrillary pathology. Taken together, these results provide evidence supporting a direct link between oxidative damage to neuronal Pin1 and the pathobiology of AD.

Original languageEnglish
Pages (from-to)918-925
Number of pages8
JournalNeurobiology of Aging
Volume27
Issue number7
DOIs
StatePublished - Jul 2006

Bibliographical note

Funding Information:
The authors would like to thank the University of Kentucky ADRC Clinical Neuropathology Core faculty for providing the brain tissue used for this study. This work was supported in part by grants from NIH [AG-05119, AG-10836 to D.A.B] and [AG17870 and AG22082 to K.P.L].

Keywords

  • Alzheimer's disease
  • Hippocampus
  • Oxidative stress
  • Peptidyl prolyl cis-trans isomerase (PPIase)
  • Tau protein

ASJC Scopus subject areas

  • Clinical Neurology
  • Geriatrics and Gerontology
  • Aging
  • General Neuroscience
  • Developmental Biology

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