HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

Hanako Tsushima, Marco Emanuele, Alice Polenghi, Alessandro Esposito, Massimo Vassalli, Andrea Barberis, Francesco Difato () and Evelina Chieregatti ()
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Hanako Tsushima: Istituto Italiano di Tecnologia
Marco Emanuele: Istituto Italiano di Tecnologia
Alice Polenghi: Istituto Italiano di Tecnologia
Alessandro Esposito: Istituto Italiano di Tecnologia
Massimo Vassalli: Institute of Biophysics, National Research Council of Italy
Andrea Barberis: Istituto Italiano di Tecnologia
Francesco Difato: Istituto Italiano di Tecnologia
Evelina Chieregatti: Istituto Italiano di Tecnologia

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8781

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