Proteomic identification of specifically carbonylated brain proteins in APPNLh/APPNLh × PS-1P264L/PS-1P264L human double mutant knock-in mice model of Alzheimer disease as a function of age

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 APPNLh/APPNLh × PS-1P246L/PS-1P246L 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.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (43 K)Download as PowerPoint slideHighlights► Aβ-induced oxidative stress is central to Alzheimer’s disease (AD) pathogenesis. ► APPNLh/APPNLh x PS-1P264L/PS-1P264L human double mutant KI mouse model was used. ► Redox proteomics identified protein targets of oxidation as a function of age. ► A number of protein targets of oxidation were also previously found in AD brain. ► Targets of oxidation may provide insights into AD progression or pathogenesis.