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

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.