Oxidative modification and down-regulation of Pin1 in Alzheimer's disease hippocampus: A redox proteomics analysis.
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 (Abeta) 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.
Sultana
Rukhsana
R
Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
Boyd-Kimball
Debra
D
Poon
H Fai
HF
Cai
Jain
J
Pierce
William M
WM
Klein
Jon B
JB
Markesbery
William R
WR
Zhou
Xiao Zhen
XZ
Lu
Kun Ping
KP
Butterfield
D Allan
DA
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016874:Neurofibrillary Tangles / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology; D040901:Proteomics; D016875:tau Proteins / Q000378:metabolism
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016875:tau Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase