Amyloid-β Induces Cdh1-Mediated Rock2 Stabilization Causing Neurodegeneration

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) and tau pathology, leading to cognitive decline.
• Rho protein kinase 2 (Rock2) increases early in AD, but its regulatory mechanism and role are unclear.

Purpose of the Study:

• To elucidate the molecular mechanism of Rock2 upregulation in AD.
• To investigate the role of Rock2 in Aβ-induced neurodegeneration and memory impairment.

Main Methods:

• Primary mouse cortical neuron cultures and *in vivo* mouse hippocampus models.
• Genetic and pharmacological inhibition of Rock2 activity.
• Analysis of cyclin dependent kinase-5 (Cdk5), Cdh1, and anaphase-promoting complex/cyclosome (APC/C) interactions.

Main Results:

• Amyloidogenic Aβ25-35 oligomers increased Rock2 accumulation and activation.
• Cdk5-mediated Cdh1 phosphorylation inactivated the APC/C, stabilizing Rock2.
• Inhibiting Rock2 rescued Aβ25-35-induced neuronal apoptosis and memory deficits.
• Modulating Cdh1 phosphorylation affected Aβ25-35 neurotoxicity, with Cdh1 inactivation exacerbating it.

Conclusions:

• The Cdk5-Cdh1 signaling pathway mediates Rock2 upregulation by amyloidogenic Aβ peptides.
• This pathway contributes to neurodegeneration and memory loss in Alzheimer's disease.