title: Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer's Disease.
abstract: It is widely accepted that amyloid β (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in Alzheimer's disease (AD), yet little is known about the contribution of APP to intracellular signaling events preceding AD pathogenesis. The data presented here demonstrate that APP expression and neuronal exposure to oligomeric Aβ42 enhance Ras/ERK signaling cascade and glycogen synthase kinase 3 (GSK-3) activation. We find that RNA interference (RNAi)-directed knockdown of APP in B103 rat neuroblastoma cells expressing APP inhibits Ras-ERK signaling and GSK-3 activation, indicating that APP acts upstream of these signal transduction events. Both ERK and GSK-3 are known to induce hyperphosphorylation of tau and APP at Thr668, and our findings suggest that aberrant signaling by APP facilitates these events. Supporting this notion, analysis of human AD brain samples showed increased expression of Ras, activation of GSK-3, and phosphorylation of APP and tau, which correlated with Aβ levels in the AD brains. Furthermore, treatment of primary rat neurons with Aβ recapitulated these events and showed enhanced Ras-ERK signaling, GSK-3 activation, upregulation of cyclin D1, and phosphorylation of APP and tau. The finding that Aβ induces Thr668 phosphorylation on APP, which enhances APP proteolysis and Aβ generation, denotes a vicious feedforward mechanism by which APP and Aβ promote tau hyperphosphorylation and neurodegeneration in AD. Based on these results, we hypothesize that aberrant proliferative signaling by APP plays a fundamental role in AD neurodegeneration and that inhibition of this would impede cell cycle deregulation and neurodegeneration observed in AD.
authors.affiliation: Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida , Tampa, FL 33613.
authors.forename: Lisa
authors.identifier: 0000-0002-4948-4451
authors.initials: L
authors.lastname: Kirouac
authors.affiliation: Institute for Memory Impairment and Neurological Disorders, Department of Neurology, University of California, Irvine , Irvine, CA 92697-4540.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Rajic
authors.affiliation: Institute for Memory Impairment and Neurological Disorders, Department of Neurology, University of California, Irvine , Irvine, CA 92697-4540.
authors.forename: David H
authors.initials: DH
authors.lastname: Cribbs
authors.affiliation: Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida , Tampa, FL 33613.
authors.forename: Jaya
authors.identifier: 0000-0003-2019-5135
authors.initials: J
authors.lastname: Padmanabhan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D018631:ras Proteins / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C054369:MAPT protein, human; C489131:Mapt protein, rat; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D019938:Cyclin D1; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D018631:ras Proteins
keywords: A-beta; Alzheimer’s disease; GSK3; Ras-MAPK signaling; amyloid precursor protein; protein phosphorylation