The Aβ1-42 peptide regulates microtubule stability independently of tau

Interference with microtubule stability by beta-amyloid peptide (A beta) has been shown to disrupt dendritic function and axonal trafficking, both early events in Alzheimer's disease. However, it is unclear whether A beta regulation of microtubule dynamics can occur independently of its action on tau. RhoA has been implicated in neurotoxicity by A beta but the mechanism by which this activation generates cytoskeletal changes is also unclear. We found that oligomeric A beta(1-42) 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 A beta was also initiated by dimerization of APP and required caspase activity, two previously characterized regulators of neurotoxicity downstream of A beta. 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 A beta. Our study reveals a novel activity of A beta on the microtubule cytoskeleton that is independent of tau and associated with pathways linked to microtubule stabilization and A beta-mediated neurotoxicity.