title: HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity.
abstract: Maintenance of neuronal polarity and regulation of cytoskeletal dynamics are vital during development and to uphold synaptic activity in neuronal networks. Here we show that soluble β-amyloid (Aβ) disrupts actin and microtubule (MT) dynamics via activation of RhoA and inhibition of histone deacetylase 6 (HDAC6) in cultured hippocampal neurons. The contact of Aβ with the extracellular membrane promotes RhoA activation, leading to growth cone collapse and neurite retraction, which might be responsible for hampered neuronal pathfinding and migration in Alzheimer's disease (AD). The inhibition of HDAC6 by Aβ increases the level of heterodimeric acetylated tubulin and acetylated tau, both of which have been found altered in AD. We also find that the loss of HDAC6 activity perturbs the integrity of axon initial segment (AIS), resulting in mislocalization of ankyrin G and increased MT instability in the AIS concomitant with loss of polarized localization of tau and impairment of action potential firing.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: Hanako
authors.initials: H
authors.lastname: Tsushima
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Emanuele
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Polenghi
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Esposito
authors.affiliation: Institute of Biophysics, National Research Council of Italy, Genoa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Vassalli
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Barberis
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Difato
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: Evelina
authors.initials: E
authors.lastname: Chieregatti
mesh_terms: D000107:Acetylation; D000199:Actins / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D020439:Growth Cones / Q000502:physiology*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D014404:Tubulin / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D016229:Amyloid beta-Peptides; D014404:Tubulin; D016875:tau Proteins; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D020742:rhoA GTP-Binding Protein