{"title":"BACE1-dependent cleavage of GABA<sub>A</sub> receptor contributes to neural hyperexcitability and disease progression in Alzheimer's disease.","authors":"Danlei Bi, Hong Bao, Xiaoli Yang, Zujun Wu, Xiaoxu Yang, Guangwei Xu, Xiaoming Liu, Zhikun Wan, Jiachen Liu, Junju He, Lang Wen, Yuying Jing, Ruijie Zhu, Zhenyu Long, Yating Rong, Dongxu Wang, Xiaoqun Wang, Wei Xiong, Guangming Huang, Feng Gao, Yong Shen","doi":"10.1016/j.neuron.2025.01.030","DOIUrl":null,"url":null,"abstract":"<p><p>Neural hyperexcitability has been clinically associated with amyloid-β (Aβ) pathology and cognitive impairment in Alzheimer's disease (AD). Here, we show that decreased GABA<sub>A</sub> receptor (GABA<sub>A</sub>R) currents are linked to hippocampal granule cell hyperexcitability in the AD mouse model APP23. Elevated levels of β-secretase (BACE1), the β-secretase responsible for generating Aβ peptides, lead to aberrant cleavage of GABA<sub>A</sub>R β1/2/3 subunits in the brains of APP23 mice and AD patients. Moreover, BACE1-dependent cleavage of the β subunits leads to a decrease in GABA<sub>A</sub>R-mediated inhibitory currents in BACE1 transgenic mice. Finally, we show that the neural hyperexcitability, Aβ load, and spatial memory deficit phenotypes of APP23 mice are significantly reduced upon the granule cell expression of a non-cleavable β3 subunit mutant. Collectively, our study establishes that BACE1-dependent cleavage of GABA<sub>A</sub>R β subunits promotes the pathological hyperexcitability known to drive neurodegeneration and cognitive impairment in the AD brain, suggesting that prevention of the cleavage could slow disease progression.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7000,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuron","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.neuron.2025.01.030","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
BACE1-dependent cleavage of GABAA receptor contributes to neural hyperexcitability and disease progression in Alzheimer's disease.
Neural hyperexcitability has been clinically associated with amyloid-β (Aβ) pathology and cognitive impairment in Alzheimer's disease (AD). Here, we show that decreased GABAA receptor (GABAAR) currents are linked to hippocampal granule cell hyperexcitability in the AD mouse model APP23. Elevated levels of β-secretase (BACE1), the β-secretase responsible for generating Aβ peptides, lead to aberrant cleavage of GABAAR β1/2/3 subunits in the brains of APP23 mice and AD patients. Moreover, BACE1-dependent cleavage of the β subunits leads to a decrease in GABAAR-mediated inhibitory currents in BACE1 transgenic mice. Finally, we show that the neural hyperexcitability, Aβ load, and spatial memory deficit phenotypes of APP23 mice are significantly reduced upon the granule cell expression of a non-cleavable β3 subunit mutant. Collectively, our study establishes that BACE1-dependent cleavage of GABAAR β subunits promotes the pathological hyperexcitability known to drive neurodegeneration and cognitive impairment in the AD brain, suggesting that prevention of the cleavage could slow disease progression.
期刊介绍：
Established as a highly influential journal in neuroscience, Neuron is widely relied upon in the field. The editors adopt interdisciplinary strategies, integrating biophysical, cellular, developmental, and molecular approaches alongside a systems approach to sensory, motor, and higher-order cognitive functions. Serving as a premier intellectual forum, Neuron holds a prominent position in the entire neuroscience community.
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