ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer’s disease mouse model  

作　　者：Xian-hua Deng Xing-yang Liu Yi-hua Wei Ke Wang Jun-rong Zhu Jia-jun Zhong Jing-yuan Zheng Rui Guo Yi-fan Zhu Qiu-hong Ye Meng-dan Wang Ying-jie Chen Jian-quan He Ze-xu Chen Shu-qiong Huang Chong-shan Lv Guo-qing Zheng Sui-feng Liu Lei Wen 

机构地区：[1]Center for Brain Sciences,The First Affiliated Hospital of Xiamen University,State Key Laboratory of Cellular Stress Biology,Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research,Institute of Neuroscience,School of Medicine,Xiamen University,Xiamen 361000,China [2]Department of Neurology,The First Affiliated Hospital of Zhejiang Chinese Medical University(Zhejiang Provincial Hospital of Chinese Medicine),Hangzhou 310006,China [3]Zhongshan Hospital,School of Medicine,Xiamen University,Xiamen 361000,China

出　　处：《Acta Pharmacologica Sinica》2024年第12期2497-2512,共16页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82274301 and 81774377);the Natural Science Foundation of Fujian Province of China(2021J01019);the National Key Research and Development Program of China(2016YFC1305903);the Program for New Century Excellent Talents in University of China(NCET-13-0505).

摘　　要：Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer’s disease(AD).Aberrations in GABAergic function and the excitatory/inhibitory(E/I)balance within the olfactory bulb(OB)have been implicated in olfactory impairment during the initial stages of AD.While the neuregulin 1(NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders,its specific role in early AD-related olfactory impairment remains incompletely understood.This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB.Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells(M/Ts)in the OB,thereby accelerating olfactory dysfunction in young adult APP/PS1 mice.Additionally,ErbB4 deficiency was associated with increased accumulation of Aβand BACE1-mediated cleavage of APP,along with enhanced CDK5 signaling in the OB.NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice.These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB,contributing to olfactory impairment in young adult APP/PS1 mice,and provide novel insights for early intervention strategies in AD.

关 键 词：Alzheimer’s disease olfactory impairment NRG1/ErbB4 signaling GABAergic transmission excitation/inhibition(E/I)imbalance 

分 类 号：R749.16[医药卫生—神经病学与精神病学]