It is widely accepted that A-beta (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 RNAi-directed knockdown of APP in B103 rat neuroblastoma cells expressing APP inhibit 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 of 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 feed-forward 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 an inhibition of this would impede cell cycle deregulation and neurodegeneration observed in AD.
Significance Statement While Aβ is fundamental to AD pathology development, Aβ-lowering drugs failed in clinical trials suggesting that additional APP-dependent mechanisms might play an important role in AD pathogenesis. Here we show that APP plays a significant role in the activation of Aβ-dependent Ras-MAPK signaling. Aβ fails to bring about the Ras-ERK activation when APP is absent from the cells. Furthermore, we show that Ras-ERK signaling induces APP and tau hyperphosphorylation, which are enhanced in the AD brains, and an inhibition of Ras-MAPK activation prevents hyperphosphorylation of tau and APP as well as neuronal cell cycle entry. These results therefore demonstrate that APP is fundamental to the cell cycle deregulation and neuropathology development observed in AD.
The authors declare no competing financial interests.