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 stAβle detyrosinated microtubules in NIH3T3 cells and this function resulted from the activation of a RhoA-dependent microtubule stAβilization pathway regulated by integrin signaling and the formin mDia1. Induction of microtubule stAβility 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 Aβolished by Rho inactivation, reinforcing a link between induction of stAβle 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 stAβilization and Aβ-mediated neurotoxicity © 2014. Published by The Company of Biologists Ltd.