title: Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer's Disease Pathology.
abstract: Alzheimer's disease (AD) is characterized by a long pre-clinical phase (20-30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention.
authors.affiliation: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.|Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Andrea F N
authors.initials: AF
authors.lastname: Rosenberger
authors.affiliation: PamGene International BV, 's-Hertogenbosch, The Netherlands.
authors.forename: Riet
authors.initials: R
authors.lastname: Hilhorst
authors.affiliation: International Drug Development Institute, Louvain-la-Neuve, Belgium.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Coart
authors.affiliation: International Drug Development Institute, Louvain-la-Neuve, Belgium.
authors.forename: Leandro
authors.initials: L
authors.lastname: García Barrado
authors.affiliation: PamGene International BV, 's-Hertogenbosch, The Netherlands.
authors.forename: Faris
authors.initials: F
authors.lastname: Naji
authors.affiliation: Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Annemieke J M
authors.initials: AJ
authors.lastname: Rozemuller
authors.affiliation: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.|Department of Epidemiology and Biostatistics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jeroen J M
authors.initials: JJ
authors.lastname: Hoozemans
authors.affiliation: Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Saskia M
authors.initials: SM
authors.lastname: van der Vies
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases
keywords: Alzheimer’s disease; peptide microarray analysis; phospho-peptides; postmortem changes; protein kinase activity; signaling pathways