Targeting MAD2B as a strategy for ischemic stroke therapy.

Area of Science:

• Neuroscience
• Cell Biology
• Ischemic Stroke Research

Background:

• Post-stroke cognitive impairment is a significant cause of disability following cerebral ischemia.
• MAD2B, an inhibitor of Cdh1/APC, influences synaptic plasticity and memory via ROCK2 in neurons.
• The specific role of MAD2B in regulating learning and memory through ROCK2 in cerebral ischemia remains unclear.

Purpose of the Study:

• To investigate the role of MAD2B in cerebral ischemia-induced cognitive dysfunction.
• To elucidate the underlying molecular mechanisms involving ROCK2.

Main Methods:

• Utilized middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) models.
• Generated MAD2B conditional knockout mice and manipulated MAD2B expression in the hippocampus via lentiviral vectors.
• Assessed cognitive function using Y-maze and Novel object recognition tests.
• Analyzed the expression of MAD2B, ROCK2, and apoptosis-related molecules.
• Intervened with ROCK2 using inhibitors and shRNA.

Main Results:

• MAD2B expression increased post-ischemia but decreased with neuroprotective agents.
• Hippocampal MAD2B deletion ameliorated cognitive deficits and motor coordination in MCAO mice.
• MAD2B deletion downregulated ROCK2/LIMK1/cofilin and reduced ischemia-induced apoptosis (BAX, cleaved caspase-3).
• ROCK2 inhibition or knockdown mimicked these effects in cultured neurons.

Conclusions:

• MAD2B exacerbates post-stroke cognitive impairment by promoting neuronal apoptosis through the ROCK2 pathway.
• Targeting MAD2B or ROCK2 may represent a therapeutic strategy for cerebral ischemia-induced neurological dysfunction.