pS396/pS404 (PHF1) tau vaccine outperforms pS199/pS202 (AT8) in rTg4510 tauopathy model.

IF 6.9 1区 医学 Q1 IMMUNOLOGY
Jonathan P Hulse, Nicole M Maphis, Julianne Peabody, Virginie Bondu, Bryce Chackerian, Kiran Bhaskar
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Abstract

Tauopathies, including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles in the brain. Site-specific phosphorylation of tau occurs early in the disease process and correlates with progressive cognitive decline, thus serving as targetable pathological epitopes for immunotherapy development. Previously, we developed a vaccine (Qβ-pT181) displaying phosphorylated Thr181 tau peptides on the surface of a Qβ bacteriophage virus-like particle (VLP) that induced robust antibody responses, cleared pathological tau, and rescued memory deficits in a transgenic mouse model of tauopathy. Here we report the characterization and comparison of two additional Qβ VLP-based vaccines targeting the dual phosphorylation sites Ser199/Ser202 (Qβ-AT8) and Ser396/Ser404 (Qβ-PHF1). Both Qβ-AT8 and Qβ-PHF1 vaccines elicited high-titer antibody responses against their pTau epitopes. However, only Qβ-PHF1 rescued cognitive deficits, reduced soluble and insoluble pathological tau, and inflammatory microgliosis in a 4.5-month rTg4510 model of FTD. Both sera from Qβ-AT8 and Qβ-PHF1 vaccinated mice were specifically reactive to tau pathology in human AD post-mortem brain sections. These studies further support the use of VLP-based immunotherapies to target pTau in AD and related tauopathies and provide potential insight into the clinical efficacy of various pTau epitopes in the development of immunotherapies.

在rTg4510 tau病变模型中,pS396/pS404 (PHF1) tau疫苗优于pS199/pS202 (AT8)。
tau病,包括阿尔茨海默病(AD)和额颞叶痴呆(FTD),在组织病理学上是由过度磷酸化的病理性tau (pTau)聚集在大脑中作为神经原纤维缠结来定义的。tau蛋白的位点特异性磷酸化发生在疾病过程的早期,与进行性认知能力下降相关,因此可以作为免疫治疗发展的可靶向病理表位。此前,我们开发了一种疫苗(Qβ- pt181),该疫苗在Qβ噬菌体病毒样颗粒(VLP)表面显示磷酸化的Thr181 tau肽,可诱导强大的抗体反应,清除病理性tau,并在转基因小鼠tau病模型中恢复记忆缺陷。在这里,我们报告了另外两种基于Qβ vlp的疫苗的特性和比较,这些疫苗靶向双磷酸化位点Ser199/Ser202 (Qβ- at8)和Ser396/Ser404 (Qβ- phf1)。Qβ-AT8和Qβ-PHF1疫苗均可引发针对其pTau表位的高滴度抗体反应。然而,在4.5个月的rTg4510 FTD模型中,只有Qβ-PHF1可以挽救认知缺陷,减少可溶性和不可溶性病理性tau和炎症性小胶质细胞增生。接种Qβ-AT8和Qβ-PHF1疫苗的小鼠血清对人阿尔茨海默病死后脑切片的tau病理有特异性反应。这些研究进一步支持使用基于vlp的免疫疗法靶向pTau治疗AD和相关的tau病变,并为各种pTau表位在免疫疗法开发中的临床疗效提供了潜在的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
NPJ Vaccines
NPJ Vaccines Immunology and Microbiology-Immunology
CiteScore
11.90
自引率
4.30%
发文量
146
审稿时长
11 weeks
期刊介绍: Online-only and open access, npj Vaccines is dedicated to highlighting the most important scientific advances in vaccine research and development.
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