Extracellular Aβ42 Oligomers Induce ROCK2 Hyperactivation Through Dual Mediation by RhoA and GzmB: Significance of Moderate ROCK2 Activity in Neural Cells.

Overview

1. Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China

Abstract

Highlights: What are the main findings? EAO induces ROCK2 hyperactivation via integrin/RhoA- and GzmB-associated processing. EAO-induced ROCK2 hyperactivation may be a key link between EAO and actin cytoskeletal dysfunction. Excessive inhibition of ROCK2 activity may result in excessive neurite outgrowth.

What are the implications of the main findings? An imbalance in ROCK2 activity may disrupt intrinsic neuronal networks. Modulating abnormal ROCK2 activity may provide a potential therapeutic strategy for AD.

Abstract: Alzheimer’s disease (AD) is characterized by neurite degeneration and neuronal death. Extracellular amyloid-β 1-42 (Aβ42) oligomers (EAO) not only disrupt the homeostasis and function of the extracellular matrix (ECM) but also damage neural cells through direct binding. Previous studies have demonstrated that EAO binding to membrane integrins reduces neuronal motility, adhesion, and neuritogenesis. To identify the key molecular switch(es) responsible for these actin cytoskeleton dysfunction-associated events, this study utilized neuronal and glial cell lines as well as AD model mice to investigate the cascade underlying EAO-induced actin cytoskeleton dysfunction. This study revealed that EAO induce the dual activation of ROCK2 through RhoA and granzyme B (GzmB) mediation, with GzmB-mediated ROCK2 activation constituting a significant component of this process. ROCK2 hyperactivation in response to EAO causes dynamic dysregulation of the actin cytoskeleton, defective neuritogenesis, and ultimately reduced cell survival, leading to disturbances in brain cell populations. However, the excessive inhibition of ROCK2 activity might cause excessive neurite outgrowth, which may disrupt intrinsic neuronal networks or normal neural transmission. Thus, the disruption of ROCK2 activity might lead to impaired neuritogenesis and disturbances in brain cell populations. The findings of this study may provide important insights into AD pathogenesis and feasible therapeutic targets.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• uniprot.org/uniprotkb, at UniProt; found in the text, “2.10. Molecular Simulation and Docking”

Data Availability Statement

The datasets and materials used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 6 keywords, 11 MeSH terms, 1 funder, 61 references.

Cite

This paper

Zheng, C., Wen, K., Li, H., Zhang, T., & Zhang, Y. (2026). Extracellular Aβ42 Oligomers Induce ROCK2 Hyperactivation Through Dual Mediation by RhoA and GzmB: Significance of Moderate ROCK2 Activity in Neural Cells. Cells, 15(15), 1379. https://doi.org/10.3390/cells15151379

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