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Alzheimer's Research & Therapy
Published in: Alzheimer's Research & Therapy 1/2018

Open Access 01-12-2018 | Research

Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated Tau-induced pathology in 3 × Tg-AD mice

Authors: Chun-ling Dai, Wen Hu, Yunn Chyn Tung, Fei Liu, Cheng-Xin Gong, Khalid Iqbal

Published in: Alzheimer's Research & Therapy | Issue 1/2018

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Abstract

Background

Accumulating evidence indicates that Tau pathology can spread from neuron to neuron by intake and coaggregation of the hyperphosphorylated Tau (p-Tau) seeds with the host neuron protein. Thus, clearance of Tau seeds by immunization with Tau antibodies could provide a potential therapeutic opportunity to block the spread of the pathology in Alzheimer’s disease (AD) and other tauopathies. We report prevention of the seeding and spread of tau pathology with mouse monoclonal antibody 43D against the N-terminal projection domain of Tau (Tau 6–18) in triple-transgenic AD (3 × Tg-AD) mice.

Methods

Female 11- to 12-month-old 3 × Tg-AD mice were intravenously immunized weekly for 6 weeks with 15 μg/injection of mouse monoclonal antibody 43D or with mouse immunoglobulin G as a control. AD p-Tau isolated from a frozen autopsied AD brain was unilaterally injected into the right hippocampus on the day of the second dose of immunization. Tau pathology and its effect on Aβ pathology were assessed by immunohistochemical staining.

Results

We found that the injection of AD p-Tau into the hippocampus of 11- to 12-month-old 3 × Tg-AD mice time-dependently induced Tau aggregation in the hippocampus and promoted the spread of Tau pathology to the contralateral hippocampus. Tau pathology was observed as early as 6 weeks after AD p-Tau injection. Tau pathology templated by AD p-Tau was thioflavin-S-positive and was about two-fold greater than that seen in naive 18-month-old 3 × Tg-AD mice; Tau pathology in the latter was thioflavin-S-negative. Immunization with Tau antibody 43D dramatically blocked AD p-Tau seeding in the ipsilateral hippocampus and inhibited its propagation to the contralateral side in 3 × Tg-AD mice. Furthermore, AD p-Tau injection enhanced the amyloid plaque load in the ipsilateral side, and immunization with 43D showed a tendency to attenuate it.

Conclusions

These findings indicate that AD p-Tau-injected 3 × Tg-AD mice represent a practical model to study the seeding and spread of Tau pathology, their effect on Aβ pathology, and the effect of Tau immunotherapy on both Tau and Aβ pathologies. Immunization with Tau antibody 43D to Tau 6–18 can prevent the seeding and spread of Tau pathology, making it a potential therapeutic treatment for AD and related tauopathies.
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Metadata
Title
Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated Tau-induced pathology in 3 × Tg-AD mice
Authors
Chun-ling Dai
Wen Hu
Yunn Chyn Tung
Fei Liu
Cheng-Xin Gong
Khalid Iqbal
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2018
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-018-0341-7

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