BACE1-dependent cleavage of GABAA receptor contributes to neural hyperexcitability and disease progression in Alzheimer's disease

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

BACE1-dependent cleavage of GABA_A receptor contributes to neural hyperexcitability and disease progression in Alzheimer's disease

Neuron. 2025 Apr 2;113(7):1051-1064.e6. doi: 10.1016/j.neuron.2025.01.030. Epub 2025 Feb 26.

Authors

Danlei Bi¹, Hong Bao², Xiaoli Yang², Zujun Wu², Xiaoxu Yang², Guangwei Xu², Xiaoming Liu², Zhikun Wan², Jiachen Liu², Junju He², Lang Wen², Yuying Jing², Ruijie Zhu², Zhenyu Long², Yating Rong², Dongxu Wang², Xiaoqun Wang³, Wei Xiong², Guangming Huang³, Feng Gao⁴, Yong Shen⁵

Affiliations

¹ Department of Neurology and Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Anhui Province Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Hefei, China. Electronic address: dbi@ustc.edu.cn.
² Department of Neurology and Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Anhui Province Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Hefei, China.
³ Department of Chemistry, University of Science and Technology of China, Hefei, China.
⁴ Department of Neurology and Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Anhui Province Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Hefei, China. Electronic address: fenggao7@ustc.edu.cn.
⁵ Department of Neurology and Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Anhui Province Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Hefei, China. Electronic address: yongshen@ustc.edu.cn.

PMID: 40015276
DOI: 10.1016/j.neuron.2025.01.030

Abstract

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_A receptor (GABA_AR) 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_AR 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_AR-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_AR 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.

Keywords: BACE1 substrate; GABRB; disinhibition; excitatory inhibitory balance; excitotoxicity; hyperactivity; hyperexcitability; β-secretase.

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Alzheimer Disease* / physiopathology
Amyloid Precursor Protein Secretases* / genetics
Amyloid Precursor Protein Secretases* / metabolism
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / genetics
Animals
Aspartic Acid Endopeptidases* / genetics
Aspartic Acid Endopeptidases* / metabolism
Disease Models, Animal
Disease Progression
Female
Hippocampus / metabolism
Humans
Male
Mice
Mice, Transgenic
Neurons* / metabolism
Neurons* / physiology
Receptors, GABA-A* / genetics
Receptors, GABA-A* / metabolism

Substances

Amyloid Precursor Protein Secretases
Receptors, GABA-A
Aspartic Acid Endopeptidases
Bace1 protein, mouse
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
BACE1 protein, human