2. Academic Validation
  3. Targeting MAD2B as a strategy for ischemic stroke therapy

Targeting MAD2B as a strategy for ischemic stroke therapy

  • J Adv Res. 2024 Jul 5:S2090-1232(24)00269-8. doi: 10.1016/j.jare.2024.07.003.
Lijing Zhang 1,  Hengzhen Cui 1,  Wandi Hu 1,  Xianfang Meng 2,  Chun Zhang 3
Affiliations

Affiliations

  • 1 Department of Neurobiology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Department of Neurobiology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: xfmeng@mails.tjmu.edu.cn.
  • 3 Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: drzhangchun@hust.edu.cn.
PMID: 38972542 DOI: 10.1016/j.jare.2024.07.003
Abstract

Introduction: Post-stroke cognitive impairment is one of the major causes of disability due to cerebral ischemia. MAD2B is an inhibitor of Cdh1/APC, and loss of Cdh1/APC function in mature neurons increases ROCK2 activity, leading to changes in synaptic plasticity and memory loss in mouse neurons. Whether MAD2B regulates learning memory capacity through ROCK2 in cerebral ischemia is not known.

Objectives: We investigated the role and mechanism of MAD2B in cerebral ischemia-induced cognitive dysfunction.

Methods: The expression of MAD2B and its downstream related molecules was detected by immunoblotting and intervened with neuroprotectants after middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R). We constructed MAD2B-cKO-specific knockout mice, knocked down and overexpressed MAD2B in mouse hippocampus by lentiviral injection in brain stereotaxis, modeled cerebral ischemia by using MCAO, and explored the role of MAD2B in post-stroke cognitive impairment (PSCI) by animal behaviors such as Y-maze and Novel object recognition test. Then the expression of MAD2B/ROCK2, downstream molecules and apoptosis-related molecules was detected. Finally, ROCK2 expression was intervened using its inhibitor and shRNA-ROCK2 lentivirus.

Results: The expression of MAD2B and its downstream molecules increased after MCAO and OGD/R. Nonetheless, this expression underwent a decline post-therapy with neuroprotective agents. Deletion of MAD2B in the hippocampus ameliorated memory and learning deficits and improved motor coordination in MCAO mice. Conversely, the overexpression of MAD2B in the hippocampus exacerbated learning and memory deficits. Deletion of MAD2B resulted in the downregulation of ROCK2/LIMK1/cofilin. It effectively reduced ischemia-induced upregulation of Bax and cleaved Caspase-3, which could be reversed by MAD2B overexpression. Inhibition or knockdown of ROCK2 expression in primary cultured neurons led to the downregulation of LIMK1/cofilin expression and reduced the expression of apoptosis-associated molecules induced by ischemia.

Conclusions: Our findings suggest that MAD2B affects neuronal Apoptosis via ROCK2, which affects neurological function and cerebral infarction.

Keywords

Cerebral ischemia; Learning and memory; MAD2B; Neuron.

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