Document Type
Article
Publication Date
2016
Keywords
Alzheimer’s disease, amyloid precursor protein, phosphoproteomics, A-beta, neurodegeneration, Gerotarget
Digital Object Identifier (DOI)
https://doi.org/10.18632/oncotarget.7380
Abstract
Amyloid Precursor Protein (APP) is regulated in a mitosis-specific manner and plays a role in proliferative signaling in cells. Though APP-derived Aβ generation has a well-established role in neurodegeneration, the mechanistic role of APP in this process is not fully understood. Here, we performed an unbiased, comprehensive analysis of the phosphoproteome signature in APP-null neuroblastoma cells (B103) compared to those expressing APP-695 isoform (B103-695) to determine if APP expression affects protein phosphorylation. Stable isotope labeling by amino acids in cell culture (SILAC) followed by mass spectrometry-based phosphoproteomic analysis with PolyMAC identified a total of 2,478 phosphopeptides in the B103 and B103-695 cell culture model system. We observed that phosphorylation of PCTAIRE-2 (CDK17), PCTAIRE-3 (CDK18), and Histone H4 are significantly elevated in B103-695 cells; western blot analysis confirmed overexpression of PCTAIREs and increased phosphorylation of Histone H4. More importantly, analysis of primary neurons treated with Aβ, as well as brain samples from MCI (mild cognitive impaired) and AD patients recapitulated these results, showing increased levels of PCTAIREs and P-Histone H4. These novel findings identify a hitherto uncharacterized mechanism by which APP and/or Aβ may promote AD neurodegeneration, and raises the possibility that their inhibition may protect against pathology development in AD.
Rights Information
This work is licensed under a Creative Commons Attribution 3.0 License.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Oncotarget, v. 7, issue 8, p. 8481-8497
Scholar Commons Citation
Chaput, Dale; Kirouac, Lisa; Stevens, Stanley M. Jr.; and Padmanabhan, Jaya, "Potential Role of PCTAIRE-2, PCTAIRE-3 and P-Histone H4 in Amyloid Precursor Protein-dependent Alzheimer Pathology" (2016). Molecular Biosciences Faculty Publications. 71.
https://digitalcommons.usf.edu/bcm_facpub/71
