HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity
Open accessAbstract
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. Retracted neurites and disorganized actin filaments are major components of senile plaques and neurofibrillary tangles—hallmarks of Alzheimer's disease. Here the authors show that soluble ß-amyloid impairs action potential firing by disrupting actin and microtubule filaments through the inhibition of HDAC6 and activation of RhoA.
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Soluble Aβ disrupts actin and microtubule dynamics via activation of RhoA and inhibition of histone deacetylase 6 in cultured hippocampal neurons.
“Similarly, soluble Aβ was reported to disrupt actin and microtubule dynamics via activation of RhoA and inhibition of histone deacetylase 6 in cultured hippocampal neurons [189].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [189]
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- Authors
- Tsushima, H., Emanuele, M., Polenghi, A., Esposito, A., Vassalli, M., Barberis, A., Difato, F., & Chieregatti, E.
- Affiliations
- Italian Institute of Technology (IT)
- National Research Council (IT)
- Corresponding author
- Difato, Francesco
- Chieregatti, Evelina
- ORCID
- Venue
- Nature Communications
- Published
- 2015-07-22
- Volume
- 6
- Issue
- 1
- Pages
- 7781-7781
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W1001294977
- Cited by
- 71
- References
- 6
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 3 · 2022: 4 · 2021: 11 · 2020: 12 · 2019: 6 · 2018: 5 · 2017: 8 · 2016: 5
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- HDAC6, RhoA, amyloid-beta, neuronal polarity, actin dynamics, microtubule dynamics, axon initial segment, ankyrin-G, acetylated tubulin, neurite retraction, growth cone collapse, Alzheimer's disease, action potential firing, hippocampal neurons, cytoskeleton regulation
- MeSH terms
- Histone Deacetylase 6, Acetylation, Actins, Animals, Histone Deacetylases, Mice, Inbred C57BL, Tubulin, Amyloid beta-Peptides, tau Proteins, Growth Cones, rhoA GTP-Binding Protein
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