Hulse Jonathan P, Maphis Nicole M, Peabody Julianne, Bondu Virginie, Chackerian Bryce, Bhaskar Kiran
Department of Molecular Genetics & Microbiology, University of New Mexico, Albuquerque, NM, USA.
Department of Neurosciences, University of New Mexico, Albuquerque, NM, USA.
NPJ Vaccines. 2025 May 13;10(1):94. doi: 10.1038/s41541-025-01147-4.
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.
tau蛋白病，包括阿尔茨海默病（AD）和额颞叶痴呆（FTD），在组织病理学上的定义是，大脑中过度磷酸化的病理性tau蛋白（pTau）聚集形成神经原纤维缠结。tau蛋白的位点特异性磷酸化在疾病过程早期就会出现，并与进行性认知衰退相关，因此可作为免疫治疗开发中可靶向的病理表位。此前，我们开发了一种疫苗（Qβ-pT181），它在Qβ噬菌体病毒样颗粒（VLP）表面展示磷酸化的苏氨酸181 tau肽段，该疫苗在tau蛋白病转基因小鼠模型中可诱导强烈的抗体反应、清除病理性tau蛋白并挽救记忆缺陷。在此，我们报告另外两种基于Qβ VLP的疫苗的特性及比较，这两种疫苗靶向双磷酸化位点丝氨酸199/丝氨酸202（Qβ-AT8）和丝氨酸396/丝氨酸404（Qβ-PHF1）。Qβ-AT8和Qβ-PHF1疫苗均能引发针对其pTau表位的高滴度抗体反应。然而，在4.5个月大的FTD rTg4510模型中，只有Qβ-PHF1能挽救认知缺陷、减少可溶性和不可溶性病理性tau蛋白以及炎症性小胶质细胞增生。接种Qβ-AT8和Qβ-PHF1疫苗的小鼠血清均能与人AD死后脑切片中的tau病理特异性反应。这些研究进一步支持使用基于VLP的免疫疗法来靶向AD及相关tau蛋白病中的pTau，并为免疫疗法开发中各种pTau表位的临床疗效提供了潜在的见解。
