title: The Aβ₁₋₄₂ peptide regulates microtubule stability independently of tau.
abstract: Interference with microtubule stability by beta-amyloid peptide (Aβ) has been shown to disrupt dendritic function and axonal trafficking, both early events in Alzheimer's disease. However, it is unclear whether Aβ regulation of microtubule dynamics can occur independently of its action on tau. RhoA has been implicated in neurotoxicity by Aβ but the mechanism by which this activation generates cytoskeletal changes is also unclear. We found that oligomeric Aβ1-42 induced the formation of stable detyrosinated microtubules in NIH3T3 cells and this function resulted from the activation of a RhoA-dependent microtubule stabilization pathway regulated by integrin signaling and the formin mDia1. Induction of microtubule stability by Aβ was also initiated by dimerization of APP and required caspase activity, two previously characterized regulators of neurotoxicity downstream of Aβ. Finally, we found that this function was conserved in primary neurons and abolished by Rho inactivation, reinforcing a link between induction of stable detyrosinated microtubules and neuropathogenesis by Aβ. Our study reveals a novel activity of Aβ on the microtubule cytoskeleton that is independent of tau and associated with pathways linked to microtubule stabilization and Aβ-mediated neurotoxicity.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pianu
authors.forename: Roger
authors.initials: R
authors.lastname: Lefort
authors.forename: Laure
authors.initials: L
authors.lastname: Thuiliere
authors.forename: Elsa
authors.initials: E
authors.lastname: Tabourier
authors.forename: Francesca
authors.initials: F
authors.lastname: Bartolini
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D000080865:Formins; D006624:Hippocampus / Q000473:pathology; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000502:physiology*; D055550:Protein Stability; D051381:Rats; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D000080865:Formins; C558298:Mapt protein, mouse; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D020169:Caspases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: APP; Amyloid beta; Aβ; Aβ1-42 peptide; Caspase; Integrin signaling; RhoA; Stable microtubules; mDia1