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

被引：24

作者：

Zhang, Denghong ^{[1
]}

Zhang, Wei ^{[2
]}

Ming, Chen ^{[3
,4
,5
]}

Gao, Xuheng ^{[1
]}

Yuan, Huilong ^{[1
]}

Lin, Xiaojie ^{[1
]}

Mao, Xinru ^{[1
]}

Wang, Chunping ^{[1
]}

Guo, Xiaoyi ^{[1
]}

Du, Ying ^{[2
]}

Shao, Lin ^{[1
]}

Yang, Renzhi ^{[6
]}

Lin, Zhihao ^{[1
]}

Wu, Xilin ^{[7
]}

Huang, Timothy Y. ^{[8
]}

Wang, Zhanxiang ^{[1
]}

Zhang, Yun-wu ^{[1
]}

Xu, Huaxi ^{[1
]}

Zhao, Yingjun ^{[1
]}

机构：

[1] Xiamen Univ, Affiliated Hosp 1, Ctr Brain Sci, Inst Neurosci,Fujian Prov Key Lab Neurodegenerat D, Xiamen 361005, Fujian, Peoples R China

[2] Fourth Mil Med Univ, Tangdu Hosp, Dept Neurol, Xian 710038, Shaanxi, Peoples R China

[3] Univ Macau, Fac Hlth Sci, Dept Publ Hlth & Med Adm, Taipa 999078, Macao, Peoples R China

[4] Univ Macau, Fac Hlth Sci, Minist Educ Frontiers Sci, Ctr Precis Oncol, Taipa, Macao, Peoples R China

[5] Univ Macau, Ctr Cognit & Brain Sci, Taipa 999078, Macao, Peoples R China

[6] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China

[7] Chongqing Univ, Chongqing 350001, Peoples R China

[8] Sanford Burnham Prebys Med Discovery Inst, Degenerat Dis Program, La Jolla, CA 92037 USA

来源：

NEURON | 2024年 / 112卷 / 10期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

NEUROFIBRILLARY TANGLES; TAU ANTIBODIES; MOUSE MODEL; PROTEIN-TAU; PATHOLOGY; DEMENTIA; PEPTIDE; PLASMA; IDENTIFICATION; A-BETA-42/40;

D O I：

10.1016/j.neuron.2024.02.017

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

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.

引用

页码：1676 / 1693.e12

页数：31

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