在rTg4510 tau病变模型中,pS396/pS404 (PHF1) tau疫苗优于pS199/pS202 (AT8)。

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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引用次数: 0

摘要

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

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.

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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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