P-tau217 correlates with neurodegeneration in Alzheimer's disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy

作者全名：Zhang, Denghong; Zhang, Wei; Ming, Chen; Gao, Xuheng; Yuan, Huilong; Lin, Xiaojie; Mao, Xinru; Wang, Chunping; Guo, Xiaoyi; Du, Ying; Shao, Lin; Yang, Renzhi; Lin, Zhihao; Wu, Xilin; Huang, Timothy Y.; Wang, Zhanxiang; Zhang, Yun-wu; Xu, Huaxi; Zhao, Yingjun

作者地址：[Zhang, Denghong; Gao, Xuheng; Yuan, Huilong; Lin, Xiaojie; Mao, Xinru; Wang, Chunping; Guo, Xiaoyi; Shao, Lin; Lin, Zhihao; Wang, Zhanxiang; Zhang, Yun-wu; Xu, Huaxi; Zhao, Yingjun] Xiamen Univ, Affiliated Hosp 1, Ctr Brain Sci, Inst Neurosci,Fujian Prov Key Lab Neurodegenerat D, Xiamen 361005, Fujian, Peoples R China; [Zhang, Wei; Du, Ying] Fourth Mil Med Univ, Tangdu Hosp, Dept Neurol, Xian 710038, Shaanxi, Peoples R China; [Ming, Chen] Univ Macau, Fac Hlth Sci, Dept Publ Hlth & Med Adm, Taipa 999078, Macao, Peoples R China; [Ming, Chen] Univ Macau, Fac Hlth Sci, Minist Educ Frontiers Sci, Ctr Precis Oncol, Taipa, Macao, Peoples R China; [Ming, Chen] Univ Macau, Ctr Cognit & Brain Sci, Taipa 999078, Macao, Peoples R China; [Yang, Renzhi] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China; [Wu, Xilin] Chongqing Univ, Chongqing 350001, Peoples R China; [Huang, Timothy Y.] Sanford Burnham Prebys Med Discovery Inst, Degenerat Dis Program, La Jolla, CA 92037 USA

通信作者：Zhao, YJ (通讯作者)，Xiamen Univ, Affiliated Hosp 1, Ctr Brain Sci, Inst Neurosci,Fujian Prov Key Lab Neurodegenerat D, Xiamen 361005, Fujian, Peoples R China.

来源：NEURON

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001243843200001

JCR分区：Q1

影响因子：14.7

年份：2024

卷号：112

期号：10

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要：Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt ADassociated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau -associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD -associated neurodegeneration.

基金机构：National Key R&D Program of China [2021ZD0202402, 2021YFA1101401]; National Natural Science Foundation of China [82071213, 92049202, 81971003, 82271457, 82171406]; Program of Lin Gang Laboratory [LG-GG-202401-ADA070000]; Key R&D Program of Fujian [2023ZQNZD018]; Program of Shaanxi Province Health Research and Innovation Team for Cognitive Dysfunction Disease [2023TD-06]; Program of Shaanxi Innovative Team for Science and Technology [2024RS-CXTD-87]; Xiamen University; University of Macau [SRG2023- 00003-FHS]; China Human Brain Banking Consortium; National Health and Disease Human Brain Tissue Resource Center; Brain Bank and Neurodegenerative Disease Research Center in China

基金资助正文：<STRONG> </STRONG>We thank Baoying Xie, Haiping Zheng, Yixian Gao, Xiang You, Qingfeng Liu, Jingru Huang, Xin Wang, and Tianying Zhang at Xiamen University and Chao Wang at Chongqing Medical University for providing technical assistance, plasmids, or discussion. This study was supported by the National Key R&D Program of China 2021YFA1101401 (Y. Zhao) , the National Key R&D Program of China 2021ZD0202402 (H.X.) , the National Natural Science Foundation of China grants (82071213 to Y. Zhao, 92049202 to H.X., 81971003 and 82271457 to W.Z., 82171406 to Y.D.) , the program of Lin Gang Laboratory LG-GG-202401-ADA070000 (Y. Zhao) , the Key R&D Program of Fujian 2023ZQNZD018 (Y. Zhang) , the program of Shaanxi Province Health Research and Innovation Team for Cognitive Dysfunction Disease (2023TD-06 to W.Z.) , the program of Shaanxi Innovative Team for Science and Technology (2024RS-CXTD-87 to W.Z.) , a start-up funding from Xiamen University to Y. Zhao, and a start-up funding from University of Macau to C.M. (SRG2023- 00003-FHS) . This study was also supported by the China Human Brain Banking Consortium, the National Health and Disease Human Brain Tissue Resource Center, and the Brain Bank and Neurodegenerative Disease Research Center in China.