TY - JOUR
T1 - Proteomic identification of specifically carbonylated brain proteins in APP NLh/APP NLh×PS-1 P264L/PS-1 P264L human double mutant knock-in mice model of Alzheimer disease as a function of age
AU - Sultana, Rukhsana
AU - Robinson, Renã A.S.
AU - Di Domenico, Fabio
AU - Abdul, Hafiz Mohmmad
AU - St. Clair, Daret K.
AU - Markesbery, William R.
AU - Cai, Jian
AU - Pierce, William M.
AU - Butterfield, D. Allan
N1 - Funding Information:
This research was supported in part by a NIH grant [ AG-05119 ] to D.A.B.
PY - 2011/10/19
Y1 - 2011/10/19
N2 - Alzheimer disease (AD) is the most common type of dementia and is characterized pathologically by the presence of neurofibrillary tangles (NFTs), senile plaques (SPs), and loss of synapses. The main component of SP is amyloid-beta peptide (Aβ), a 39 to 43 amino acid peptide, generated by the proteolytic cleavage of amyloid precursor protein (APP) by the action of beta- and gamma-secretases. The presenilins (PS) are components of the γ-secretase, which contains the protease active center. Mutations in PS enhance the production of the Aβ42 peptide. To date, more than 160 mutations in PS1 have been identified. Many PS mutations increase the production of the β-secretase-mediated C-terminal (CT) 99 amino acid-long fragment (CT99), which is subsequently cleaved by γ-secretase to yield Aβ peptides. Aβ has been proposed to induce oxidative stress and neurotoxicity. Previous studies from our laboratory and others showed an age-dependent increase in oxidative stress markers, loss of lipid asymmetry, and Aβ production and amyloid deposition in the brain of APP/PS1 mice. In the present study, we used APP NLh/APP NLh×PS-1 P246L/PS-1 P246L human double mutant knock-in APP/PS-1 mice to identify specific targets of brain protein carbonylation in an age-dependent manner. We found a number of proteins that are oxidatively modified in APP/PS1 mice compared to age-matched controls. The relevance of the identified proteins to the progression and pathogenesis of AD is discussed.
AB - Alzheimer disease (AD) is the most common type of dementia and is characterized pathologically by the presence of neurofibrillary tangles (NFTs), senile plaques (SPs), and loss of synapses. The main component of SP is amyloid-beta peptide (Aβ), a 39 to 43 amino acid peptide, generated by the proteolytic cleavage of amyloid precursor protein (APP) by the action of beta- and gamma-secretases. The presenilins (PS) are components of the γ-secretase, which contains the protease active center. Mutations in PS enhance the production of the Aβ42 peptide. To date, more than 160 mutations in PS1 have been identified. Many PS mutations increase the production of the β-secretase-mediated C-terminal (CT) 99 amino acid-long fragment (CT99), which is subsequently cleaved by γ-secretase to yield Aβ peptides. Aβ has been proposed to induce oxidative stress and neurotoxicity. Previous studies from our laboratory and others showed an age-dependent increase in oxidative stress markers, loss of lipid asymmetry, and Aβ production and amyloid deposition in the brain of APP/PS1 mice. In the present study, we used APP NLh/APP NLh×PS-1 P246L/PS-1 P246L human double mutant knock-in APP/PS-1 mice to identify specific targets of brain protein carbonylation in an age-dependent manner. We found a number of proteins that are oxidatively modified in APP/PS1 mice compared to age-matched controls. The relevance of the identified proteins to the progression and pathogenesis of AD is discussed.
KW - Alzheimer's disease
KW - Amyloid β-peptide
KW - Oxidative stress
KW - Presenilin-1
KW - Protein carbonyls
KW - Redox proteomics
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U2 - 10.1016/j.jprot.2011.06.015
DO - 10.1016/j.jprot.2011.06.015
M3 - Article
C2 - 21726674
AN - SCOPUS:80054871710
SN - 1874-3919
VL - 74
SP - 2430
EP - 2440
JO - Journal of Proteomics
JF - Journal of Proteomics
IS - 11
ER -