GABAergic signaling abnormalities in a novel CLU mutation Alzheimer's disease mouse model

Chunxia Chen; Xihe Tang; Zhaohui Lan; Wan Chen; Hua Su; Weidong Li; Yaoxuan Li; Xing Zhou; Hong Gao; Xinwei Feng; Ying Guo; Meicun Yao; Wenbin Deng

doi:10.1016/j.trsl.2023.05.003

GABAergic signaling abnormalities in a novel CLU mutation Alzheimer's disease mouse model

Transl Res. 2023 Oct:260:32-45. doi: 10.1016/j.trsl.2023.05.003. Epub 2023 May 19.

Authors

Chunxia Chen¹, Xihe Tang², Zhaohui Lan³, Wan Chen⁴, Hua Su⁵, Weidong Li³, Yaoxuan Li⁶, Xing Zhou⁷, Hong Gao⁸, Xinwei Feng⁸, Ying Guo⁸, Meicun Yao⁸, Wenbin Deng⁹

Affiliations

¹ 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.
² 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.
³ Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, and Brain Science and Technology Research Center, Bio-X Institutes, Institute of Psychology and Behavioral Sciences, Shanghai Jiao Tong University, Shanghai, P. R. China.
⁴ Department of Emergency, The People's Hospital of Guangxi Zhuang Autonomous Region & Guangxi Academy of Medical Sciences, Nanning, Guangxi, P. R. China.
⁵ Department of Pharmacology, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning, P. R. China.
⁶ Department of Neurology, The People's Hospital of Guangxi Zhuang Autonomous Region & Guangxi Academy of Medical Sciences, Nanning, Guangxi, P. R. China.
⁷ Department of pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region & Guangxi Academy of Medical Sciences, Nanning, Guangxi P. R. China.
⁸ School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong P. R. China.
⁹ School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong P. R. China. Electronic address: dengwb5@mail.sysu.edu.cn.

PMID: 37211336
DOI: 10.1016/j.trsl.2023.05.003

Abstract

The CLU rs11136000C mutation (CLU^C) is the third most common risk factor for Alzheimer's disease (AD). However, the mechanism by which CLU^C leads to abnormal GABAergic signaling in AD is unclear. To address this question, this study establishes the first chimeric mouse model of CLU^C AD. Examination of grafted CLU^C medial ganglionic eminence progenitors (CLU^C hiMGEs) revealed increased GAD65/67 and a high frequency of spontaneous releasing events. CLU^C 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^C AD using a novel humanized animal model and suggest sphingolipid signaling over-activation as a potential mechanism of GABAergic signaling disorder.

Keywords: Alzheimer's disease; CLU; Gabrα2; Lipid metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / genetics
Animals
Clusterin / genetics
Clusterin / metabolism
Cognitive Dysfunction*
Disease Models, Animal
Humans
Mice
Mutation
Receptors, GABA-A / genetics
Risk Factors

Substances

Clusterin
Receptors, GABA-A
CLU protein, human