Subtype‑specific neurons from patient iPSCs display distinct neuropathological features of Alzheimer’s disease  

作　　者：Ran Tao Chunmei Yue Zhijie Guo Wenke Guo Yao Yao Xianfa Yang Zhen Shao Chao Gao Jianqing Ding Lu Shen Shengdi Chen Naihe Jing 

机构地区：[1]Guangzhou National Laboratory,Guangzhou International Bio Island,No.9 Xing Dao Huan Bei Road,Guangdong Province 510005,China [2]Suzhou Yuanzhan Biotechs,Suzhou 215000,China [3]CAS Key Laboratory of Computational Biology,Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences,Shanghai 200031,China [4]University of Chinese Academy of Sciences,Beijing 100049,China [5]XellSmart Biomedical(Suzhou)Co.,Ltd,Suzhou 215000,China [6]Center for Cell Lineage and Development,CAS Key Laboratory of Regenerative Biology,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,New Zealand Joint Laboratory On Biomedicine and Health,Guangzhou Institutes of Biomedicine and Health,GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre,Chinese Academy of Sciences,Guangzhou 510530,China [7]Department of Neurology&Institute of Neurology,RuiJin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200020,China [8]Department of Neurology,Xiangya Hospital,Central South University,Changsha,China [9]National Clinical Research Center for Geriatric Disorders,Central South University,Changsha 410028,China [10]Lab for Translational Research of Neurodegenerative Diseases,Shanghai Institute for Advanced Immunochemical Studies(SIAIS),Shanghai Tech University,Shanghai 200031,China

出　　处：《Cell Regeneration》2024年第1期150-166,共17页细胞再生(英文)

基　　金：National Key Basic Research and Development Program of China(2019YFA0801402,2018YFA0800100,2018YFA0107200,2018YFA0801402);Major Project of Guangzhou National Laboratory(GZNL2023A02005);Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16020501,XDA16020404);National Natural Science Foundation of China(31800854,32130030,31900454)。

摘　　要：Alzheimer’s disease(AD)is a progressive neurodegenerative disorder characterized by massive neuronal loss in the brain.Both cortical glutamatergic neurons and basal forebrain cholinergic neurons(BFCNs)in the AD brain are selectively vulnerable.The degeneration and dysfunction of these two subtypes of neurons are closely associated with the cognitive decline of AD patients.The determination of cellular and molecular mechanisms involved in AD pathogenesis,especially in the early stage,will largely facilitate the understanding of this disease and the develop-ment of proper intervention strategies.However,due to the inaccessibility of living neurons in the brains of patients,it remains unclear how cortical glutamatergic neurons and BFCNs respond to pathological stress in the early stage of AD.In this study,we established in vitro differentiation systems that can efficiently differentiate patient-derived iPSCs into BFCNs.We found that AD-BFCNs secreted less Aβpeptide than cortical glutamatergic neurons did,even though the Aβ42/Aβ40 ratio was comparable to that of cortical glutamatergic neurons.To further mimic the neuro-toxic niche in AD brain,we treated iPSC-derived neurons with Aβ42 oligomer(AβO).BFCNs are less sensitive to AβO induced tau phosphorylation and expression than cortical glutamatergic neurons.However,AβO could trigger apoptosis in both AD-cortical glutamatergic neurons and AD-BFCNs.In addition,AD iPSC-derived BFCNs and cortical glutamatergic neurons exhibited distinct electrophysiological firing patterns and elicited different responses to AβO treatment.These observations revealed that subtype-specific neurons display distinct neuropathological changes during the progression of AD,which might help to understand AD pathogenesis at the cellular level.

关 键 词：Alzheimer’s disease(AD) IPSC Cellular model Basal forebrain cholinergic neuron(BFCN) CORTICAL 

分 类 号：R74[医药卫生—神经病学与精神病学]