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

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

doi:10.1016/j.neurobiolaging.2005.05.005

« Previous Next »Neurobiology of Aging
Volume 27, Issue 7 , Pages 918-925, July 2006

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

Rukhsana Sultana
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
- Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA
Debra Boyd-Kimball
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
- Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA
H. Fai Poon
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
- Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA
Jain Cai
- Department of Pharmacology, University of Louisville, School of Medicine and VAMC, Louisville, KY, USA
William M. Pierce
- Department of Pharmacology, University of Louisville, School of Medicine and VAMC, Louisville, KY, USA
Jon B. Klein
- Core Proteomics Laboratory, University of Louisville, Louisville, KY, USA
William R. Markesbery
- Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA
- Departments of Neurology and Pathology, University of Kentucky, Lexington, KY 40536, USA
Xiao Zhen Zhou
- Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02115, USA
Kun Ping Lu
- Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02115, USA
D. Allan Butterfield
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA
- Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA
- Corresponding author. Tel.: +1 859 257 3184; fax: +1 859 257 5876.

Received 3 December 2004; received in revised form 25 April 2005; accepted 2 May 2005. published online 14 June 2005.

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.

Keywords: Alzheimer's disease, Tau protein, Peptidyl prolyl cis–trans isomerase (PPIase), Hippocampus, Oxidative stress