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.
Pubmed ID: 28374012 RIS Download
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View all literature mentionsThis monoclonal targets MAP2
View all literature mentionsThis monoclonal targets Hras1
View all literature mentionsThis polyclonal targets Tau, phospho (Thr231)
View all literature mentionsThis monoclonal targets Histone H3
View all literature mentionsThis monoclonal targets GSK-3alpha/beta
View all literature mentionsThis polyclonal targets Phospho-GSK-3alpha/beta (Ser21/9)
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis polyclonal targets Human APP, phospho (Thr668)
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View all literature mentionsThis polyclonal targets rabbit IgG
View all literature mentionsThis polyclonal targets mouse IgG
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
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View all literature mentionsCell line B103 is a Cancer cell line with a species of origin Rattus norvegicus (Rat)
View all literature mentionsThis monoclonal targets beta-Amyloid 1-16
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View all literature mentionsCell line B103 is a Cancer cell line with a species of origin Rattus norvegicus (Rat)
View all literature mentionsThis polyclonal targets Tau, phospho (Thr231)
View all literature mentionsThis monoclonal targets MAP2
View all literature mentionsThis monoclonal targets Hras1
View all literature mentionsThis monoclonal targets Histone H3
View all literature mentionsThis monoclonal targets GSK-3alpha/beta
View all literature mentionsThis polyclonal targets Phospho-GSK-3alpha/beta (Ser21/9)
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis polyclonal targets Human APP, phospho (Thr668)
View all literature mentionsThis monoclonal targets CCND1
View all literature mentionsThis monoclonal targets GAPDH antibody produced in mouse
View all literature mentionsThis monoclonal targets beta-Actin
View all literature mentionsThis monoclonal targets α-Tubulin
View all literature mentionsThis polyclonal targets rabbit IgG
View all literature mentionsThis polyclonal targets mouse IgG
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
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