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

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

doi:10.1016/j.neuron.2024.02.017

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

Neuron. 2024 Mar 12:S0896-6273(24)00127-2. doi: 10.1016/j.neuron.2024.02.017. Online ahead of print.

Authors

Denghong Zhang¹, Wei Zhang², Chen Ming³, Xuheng Gao¹, Huilong Yuan¹, Xiaojie Lin¹, Xinru Mao¹, Chunping Wang¹, Xiaoyi Guo¹, Ying Du², Lin Shao¹, Renzhi Yang⁴, Zhihao Lin¹, Xilin Wu⁵, Timothy Y Huang⁶, Zhanxiang Wang¹, Yun-Wu Zhang¹, Huaxi Xu¹, Yingjun Zhao⁷

Affiliations

¹ Center for Brain Sciences, the First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
² Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
³ Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR 999078, China; Ministry of Education Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Macao SAR 999078, China; Centre for Cognitive and Brain Sciences, University of Macau, Macao SAR 999078, China.
⁴ Institute for Brain Science and Disease, Chongqing Medical University, Chongqing 400016, China.
⁵ Department of Neurology, Center for Cognitive Neurology, Institute of Clinical Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China.
⁶ Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
⁷ Center for Brain Sciences, the First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Medicine, Xiamen University, Xiamen, Fujian 361005, China. Electronic address: yjzhao@xmu.edu.cn.

PMID: 38513667
DOI: 10.1016/j.neuron.2024.02.017

Abstract

Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated 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.

Keywords: Alzheimer’s disease; cell death; cognitive impairment; immunotherapy; motor dysfunction; neurodegeneration; neurodegenerative disease; p-tau217; tau; tauopathy.