• Chunxia Chen, Xihe Tang, Zhaohui Lan, Wan Chen, Hua Su, Weidong Li, Yaoxuan Li, Xing Zhou, Hong Gao, Xinwei Feng, Ying Guo, Meicun Yao, and Wenbin Deng.
• School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong P. R. China; Department of pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region & Guangxi Academy of Medical Sciences, Nanning, Guangxi P. R. China.
• Transl Res. 2023 Oct 1; 260: 324532-45.

AbstractThe CLU rs11136000C mutation (CLUC) is the third most common risk factor for Alzheimer's disease (AD). However, the mechanism by which CLUC leads to abnormal GABAergic signaling in AD is unclear. To address this question, this study establishes the first chimeric mouse model of CLUC AD. Examination of grafted CLUC medial ganglionic eminence progenitors (CLUC hiMGEs) revealed increased GAD65/67 and a high frequency of spontaneous releasing events. CLUC hiMGEs also impaired cognition in chimeric mice and caused AD-related pathologies. The expression of GABA A receptor, subunit alpha 2 (Gabrα2) was higher in chimeric mice. Interestingly, cognitive impairment in chimeric mice was reversed by treatment with pentylenetetrazole, which is a GABA A receptor inhibitor. Taken together, these findings shed light on the pathogenesis of CLUC AD using a novel humanized animal model and suggest sphingolipid signaling over-activation as a potential mechanism of GABAergic signaling disorder.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

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