Passive immunization inhibits tau phosphorylation and improves recognition learning and memory in 3xTg-AD mice

Longfei Li; Jin Miao; Yanli Jiang; Chun-Ling Dai; Khalid Iqbal; Fei Liu; Dandan Chu

doi:10.1016/j.expneurol.2023.114337

Passive immunization inhibits tau phosphorylation and improves recognition learning and memory in 3xTg-AD mice

Exp Neurol. 2023 Apr:362:114337. doi: 10.1016/j.expneurol.2023.114337. Epub 2023 Jan 27.

Authors

Longfei Li¹, Jin Miao², Yanli Jiang¹, Chun-Ling Dai³, Khalid Iqbal³, Fei Liu⁴, Dandan Chu⁵

Affiliations

¹ Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
² Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA; Laboratory Animal Center, Nantong University, Nantong 226001, China.
³ Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
⁴ Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA. Electronic address: Fei.liu@opwdd.ny.gov.
⁵ Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA. Electronic address: chudd@ntu.edu.cn.

PMID: 36717015
DOI: 10.1016/j.expneurol.2023.114337

Abstract

Tau pathology is essential in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Tau immunotherapy aimed at reducing the progression of tau pathology provides a potential therapeutic strategy for treating these diseases. By screening monoclonal antibodies 43D, 63B, 39E10, and 77G7 that recognize epitopes ranging from tau's N-terminus to C-terminus, we found the 77G7, which targets the microtubule-binding domain promoted tau clearance in a dose-dependent manner by entering neuronal cells in vitro. Intra-cerebroventricular injection of 77G7 antibody reduced tau levels in the wild-type FVB mouse brain. Without influencing the levels of detergent-insoluble and aggregated tau, intravenous injection of 77G7 reduced tau hyperphosphorylation in the brain and improved novel object recognition but not spatial learning and memory in 15-18-month-old 3xTg-AD mice. These studies suggest that epitopes recognized by tau antibodies are crucial for the efficacy of immunotherapy. Immunization with antibody 77G7 provides a novel potential opportunity for tau-directed immunotherapy of AD and related tauopathies.

Keywords: 77G7; Alzheimer's disease; Novel object recognition; Tau immunotherapy; Tau phosphorylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / pathology
Animals
Antibodies, Monoclonal / pharmacology
Disease Models, Animal
Epitopes
Immunization, Passive
Mice
Mice, Transgenic
Phosphorylation
Tauopathies*
tau Proteins / metabolism

Substances

tau Proteins
Antibodies, Monoclonal
Epitopes