title: Potential role of PCTAIRE-2, PCTAIRE-3 and P-Histone H4 in amyloid precursor protein-dependent Alzheimer pathology.
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.
authors.affiliation: Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Chaput
authors.affiliation: Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kirouac
authors.affiliation: Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Stevens
authors.affiliation: Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
authors.forename: Jaya
authors.initials: J
authors.lastname: Padmanabhan
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D060825:Cognitive Dysfunction / Q000378:metabolism / Q000473:pathology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006657:Histones; D018844:Cyclin-Dependent Kinases; C109207:PCTAIRE-2 protein kinase; C089464:PCTAIRE-3 protein kinase
keywords: A-beta; Alzheimer’s disease; Gerotarget; amyloid precursor protein; neurodegeneration; phosphoproteomics