Amyloid-beta precursor protein mediates neuronal toxicity of amyloid beta through Go protein activation

Neurobiology of Aging
Francisco Sola VigoA Lorenzo

Abstract

Amyloid beta (Abeta) is a metabolic product of amyloid-beta precursor protein (APP). Deposition of Abeta in the brain and neuronal degeneration are characteristic hallmarks of Alzheimer's disease (AD). Abeta induces neuronal degeneration, but the mechanism of neurotoxicity remains elusive. Here we show that overexpression of APP renders hippocampal neurons vulnerable to Abeta toxicity. Deletion of the extracellular Abeta sequence of APP prevents binding of APP to Abeta, and abolishes toxicity. Abeta toxicity is also abrogated by deletion of the cytoplasmic domain of APP, or by deletions comprising the Go protein-binding sequence of APP. Treatment with Pertussis toxin (PTX) abrogates APP-dependent toxicity of Abeta. Overexpression of PTX-insensitive Galpha-o subunit, but not Galpha-i subunit, of G protein restores Abeta toxicity in the presence of PTX, and this requires the integrity of APP-binding site for Go protein. Altogether, these experiments indicate that interaction of APP with toxic Abeta-species promotes toxicity in hippocampal neurons by a mechanism that involves APP-mediated Go protein activation, revealing an Abeta-receptor-like function of APP directly implicated in neuronal degeneration in AD.

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Citations

Oct 1, 2011·Experimental Brain Research·Silke BrunholzGerardo Morfini
Oct 30, 2008·The Journal of Biological Chemistry·Bruce A Yankner, Tao Lu
Jun 14, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jenna M RamakerPhilip F Copenhaver
Feb 4, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Carole DeytsAngèle T Parent
May 21, 2013·FEBS Letters·Natalia N Nalivaeva, Anthony J Turner
Apr 16, 2016·Molecular Neurobiology·Romina María UrangaGabriela Alejandra Salvador
Mar 19, 2015·Frontiers in Cellular Neuroscience·Ilaria CanobbioGiordano Pula
Apr 5, 2018·Acta Neuropathologica Communications·Alejandro Ruiz-RiquelmeJoel C Watts
Nov 15, 2018·Aging·Elena Anahi Bignante, Alfredo Lorenzo
Jan 1, 2008·Cell Adhesion & Migration·Quan-Hong MaGavin S Dawe
Jul 13, 2016·The Journal of Biological Chemistry·Valerie T RamírezNibaldo C Inestrosa
Dec 23, 2016·Frontiers in Molecular Neuroscience·Thomas Preat, Valérie Goguel
Feb 16, 2017·Frontiers in Molecular Neuroscience·Philip F Copenhaver, Donat Kögel
May 21, 2019·Frontiers in Aging Neuroscience·Patrícia G de OliveiraSandra I Vieira
Dec 10, 2016·Frontiers in Molecular Neuroscience·Jenna M RamakerPhilip F Copenhaver

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