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.
Department of neurosurgery, The People's Hospital of Guangxi Zhuang Autonomous Region & Guangxi Academy of Medical Sciences, Nanning, Guangxi P. R. China; Department of neurosurgery, Aviation General Hospital, Beijing, P. R. China.
Transl Res. 2023 Oct;260:32-45. doi: 10.1016/j.trsl.2023.05.003. Epub 2023 May 19.
The CLU rs11136000C mutation (CLU) is the third most common risk factor for Alzheimer's disease (AD). However, the mechanism by which CLU leads to abnormal GABAergic signaling in AD is unclear. To address this question, this study establishes the first chimeric mouse model of CLU AD. Examination of grafted CLU medial ganglionic eminence progenitors (CLU hiMGEs) revealed increased GAD65/67 and a high frequency of spontaneous releasing events. CLU 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 CLU AD using a novel humanized animal model and suggest sphingolipid signaling over-activation as a potential mechanism of GABAergic signaling disorder.
CLU rs11136000C 突变（CLU）是阿尔茨海默病（AD）的第三个最常见的风险因素。然而，CLU 导致 AD 中异常 GABA 能信号的机制尚不清楚。为了解决这个问题，本研究建立了第一个 CLU 阿尔茨海默病嵌合小鼠模型。对移植的 CLU 内侧神经节隆起祖细胞（CLU hiMGEs）的检查显示 GAD65/67 增加和自发释放事件的高频发生。CLU hiMGEs 还损害了嵌合小鼠的认知功能，并引起了 AD 相关的病理。GABA A 受体亚单位 α 2（Gabrα2）在嵌合小鼠中的表达更高。有趣的是，戊四氮治疗可逆转嵌合小鼠的认知障碍，戊四氮是 GABA A 受体抑制剂。总之，这些发现使用新型的人类化动物模型阐明了 CLU AD 的发病机制，并提示鞘脂信号过度激活可能是 GABA 能信号紊乱的潜在机制。
