The β-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism
Abstract
Neuritic abnormalities are a major hallmark of Alzheimer's disease (AD) pathology. Accumulation of beta-amyloid protein (Abeta) in the brain causes changes in neuritic processes in individuals with this disease. In this study, we show that Abeta decreases neurite outgrowth from SH-SY5Y human neuroblastoma cells. To explore molecular pathways by which Abeta alters neurite outgrowth, we examined the activation and localization of RhoA and Rac1 which regulate the level and phosphorylation of the collapsin response mediator protein-2 (CRMP-2). Abeta increased the levels of the GTP-bound (active) form of RhoA in SH-SY5Y cells. This increase in GTP-RhoA correlated with an increase in an alternatively spliced form of CRMP-2 (CRMP-2A) and its threonine phosphorylated form. Both a constitutively active form of Rac1 (CA-Rac1) and the Rho kinase inhibitor, Y27632, decreased levels of the CRMP-2A variant and decreased threonine phosphorylation caused by Abeta stimulation. The amount of tubulin bound to CRMP-2 was decreased in the presence of Abeta but Y27632 increased the levels of tubulin bound to CRMP-2. Increased levels of both RhoA and CRMP-2 were found in neurons surrounding amyloid plaques in the cerebral cortex of the APP(Swe) Tg2576 mice. We found that there was an increase in threonine phosphorylation of CRMP-2 in Tg2576 mice and the increase correlated with a decrease in the ability of CRMP-2 to bind tubulin. The results suggest that Abeta-induced neurite outgrowth inhibition m…
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Exposing human neuroblastoma cells to Aβ increases RhoA activation and subsequent inhibitory CHRM-2 phosphorylation, leading to dystrophic changes in neurite morphology that are reversed by ROCK inhibition using Y27632.
“Exposing human neuroblastoma cells to Aβ was found to increase RhoA activation and subsequent inhibitory CHRM-2 phosphorylation, leading to dystrophic changes in neurite morphology that were reversed by ROCK inhibition using Y27632 [184].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [184]
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“…to: David H. Small, PhD, Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800,Victoria, Australia E-mail: david.small@med.monash.edu.au Neuritic abnormalities are a major hallmark of Alzheimer’s disease (AD) pathology.”
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- Authors
- Petratos, S., Li, Q.-X., George, A. J., Hou, X., Kerr, M. L., Unabia, S. E., Hatzinisiriou, I., Maksel, D., Aguilar, M.-I., & Small, D. H.
- Affiliations
- The University of Melbourne (AU)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-11-13
- Volume
- 131
- Issue
- 1
- Pages
- 90-108
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2081903103
- Cited by
- 197
- References
- 14
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 9 · 2023: 4 · 2022: 11 · 2021: 12 · 2020: 14 · 2019: 8 · 2018: 13 · 2017: 9 · 2016: 15 · 2015: 13 · 2014: 14 · 2013: 8 · 2012: 15
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- eCite Digital Repository (University of Tasmania) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- amyloid-beta, Alzheimer's disease, CRMP2, RhoA, Rac1, Rho GTPases, neurite outgrowth, threonine phosphorylation, tubulin binding, Rho kinase, Y-27632, APP transgenic mice, amyloid plaques, SH-SY5Y cells
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Mice, Transgenic, Nerve Tissue Proteins, Phosphorylation, Tubulin, Tumor Cells, Cultured, Signal Transduction, Amyloid beta-Peptides, Neurites, GTPase-Activating Proteins, rhoA GTP-Binding Protein, rac1 GTP-Binding Protein, Intercellular Signaling Peptides and Proteins, Cell Size, Mice
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