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.

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    Utton MA, Vandecandelaere A, Wagner U, Reynolds CH, Gibb GM, Miller CC, Bayley PM, Anderton BH (1997 ) Phosphorylation of tau by glycogen synthase kinase 3beta affects the ability of tau to promote microtubule self-assembly. Biochem J 323: (Pt 741–747.

    Not in our library10.1042/bj3230741

88. 88.

    Vincent I, Jicha G, Rosado M, Dickson DW (1997 ) Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer’s disease brain. J Neurosci 17:3588–3598.

    Not in our library10.1523/jneurosci.17-10-03588.1997

89. 89.

    Walsh DM, Selkoe DJ (2004 ) Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration. Prot Pept Lett 11:213–228.

    Not in our library10.2174/0929866043407174

90. 90.

    Wildsmith KR, Holley M, Savage JC, Skerrett R, Landreth GE (2013 ) Evidence for impaired amyloid beta clearance in Alzheimer’s disease. Alzheimer’s Res Ther 5:33

    Not in our library10.1186/alzrt187

91. 91.

    Zhou F, Gong K, Song B, Ma T, van Laar T, Gong Y, Zhang L (2012 ) The APP intracellular domain (AICD) inhibits Wnt signalling and promotes neurite outgrowth. Biochim Biophys Acta 1823:1233–1241.

    Not in our library10.1016/j.bbamcr.2012.05.011

Cited by papers we hold 3

• The duality of amyloid-β: its role in normal and Alzheimer’s disease states · 2024
  No notice
• Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines · 2020
  Not checked
• Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer · 2020
  No notice

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