用Qβ病毒样颗粒疫苗靶向苏氨酸181处磷酸化的tau蛋白是安全的，具有高度免疫原性，并能减轻小鼠和恒河猴的疾病严重程度。
Targeting of phosphorylated tau at threonine 181 by a Qβ virus-like particle vaccine is safe, highly immunogenic, and reduces disease severity in mice and rhesus macaques.
作者信息
Maphis Nicole M, Hulse Jonathan, Peabody Julianne, Dadras Somayeh, Whelpley Madelin J, Kandath Manas, Wilson Colin, Hobson Sasha, Thompson Jeff, Poolsup Suttinee, Beckman Danielle, Ott Sean P, Watanabe Jennifer W, Usachenko Jodie L, Van Rompay Koen K, Morrison John, Selwyn Reed, Rosenberg Gary, Knoefel Janice, Chackerian Bryce, Bhaskar Kiran
机构信息
Department of Neuroscience, 1 University of New Mexico, Albuquerque, New Mexico, USA.
Department of Molecular Genetics and Microbiology, 1 University of New Mexico, Albuquerque, New Mexico, USA.
出版信息
Alzheimers Dement. 2025 Mar;21(3):e70101. doi: 10.1002/alz.70101.
INTRODUCTION
Pathological accumulation of tau (pTau) contributes to various tauopathies, including Alzheimer's disease (AD), and correlates with cognitive decline. A rapid surge in tau-targeted approaches via anti-sense oligonucleotides, active/passive immunotherapies suggests that targeting p-Tau is a viable strategy against tauopathies.
METHOD
We describe a multi-species validation of our previously described Qß virus-like particle (VLP)-based vaccine technology targeting phosphorylated tau on threonine 181 (pT181-Qß).
RESULTS
Two vaccine doses of pT181-Qß, without any adjuvants, elicited robust antibody responses in two different mouse models of tauopathy (PS19 and hTau) and rhesus macaques. In mouse models, vaccination reduced AT180+ hyperphosphorylated, Sarkosyl insoluble, Gallyas silver positive tau, inflammasomes/neuroinflammation, and improved recognition memory and motor function without inducing adverse T-cell activation. Anti-pT181 antibodies are reactive to pTau in human AD brains, engage pT181+ tau in human brain lysates, and are central nervous system bioavailable.
DISCUSSION
Our results suggest the translational utility of pT181-Qß against tauopathies.
HIGHLIGHTS
Icosahedral display of phosphorylated tau at threonine 181 (pT181) Qß virus-like particle surface ("pT181-Qß" vaccine) induces a robust immune response in mice and in non-human primates (NHPs) pT181-Qß vaccination reduces pathological tau (pTau) and brain atrophy, and improves memory and motor function in PS19 and hTau mice. pT181-Qß vaccination-induced immunoglobulin Gs (IgGs) are safe, Th2 skewed (anti-inflammatory), specific to pTau in human AD brain, and efficiently engage pT181 in NHPs and human brain lysate. pT181 tau in human plasma correlates with the neurofilament light in subjects with mild cognitive impairment (MCI)-suggesting the presence of pT181-Qß vaccine target in the early disease state.
引言
tau蛋白（pTau）的病理性积累会导致包括阿尔茨海默病（AD）在内的各种tau蛋白病，并与认知能力下降相关。通过反义寡核苷酸、主动/被动免疫疗法等针对tau蛋白的方法迅速涌现，这表明靶向p - Tau是对抗tau蛋白病的一种可行策略。
方法
我们描述了对我们之前描述的基于Qβ病毒样颗粒（VLP）的疫苗技术的多物种验证，该技术靶向苏氨酸181位点的磷酸化tau蛋白（pT181 - Qβ）。
结果
两剂pT181 - Qβ疫苗，无需任何佐剂，在两种不同的tau蛋白病小鼠模型（PS19和hTau）和恒河猴中引发了强烈的抗体反应。在小鼠模型中，接种疫苗减少了AT180 + 过度磷酸化、不溶于 Sarkosyl、Gallyas银染色阳性的tau蛋白、炎性小体/神经炎症，并改善了识别记忆和运动功能，且未诱导不良的T细胞激活。抗pT181抗体对人类AD大脑中的pTau有反应，能结合人脑海马体中的pT181 + tau蛋白，并且在中枢神经系统中具有生物利用度。
讨论
我们的结果表明pT181 - Qβ对tau蛋白病具有转化应用价值。
要点
在Qβ病毒样颗粒表面二十面体展示苏氨酸181位点的磷酸化tau蛋白（pT181）（“pT181 - Qβ”疫苗）在小鼠和非人类灵长类动物（NHPs）中诱导强烈的免疫反应。pT181 - Qβ疫苗接种可减少病理性tau蛋白（pTau）和脑萎缩，并改善PS19和hTau小鼠的记忆和运动功能。pT181 - Qβ疫苗接种诱导的免疫球蛋白G（IgG）是安全的，偏向Th2（抗炎），对人类AD大脑中的pTau具有特异性，并能有效结合NHPs和人脑海马体中的pT181。人类血浆中的pT181 tau蛋白与轻度认知障碍（MCI）受试者的神经丝轻链相关，这表明在疾病早期状态存在pT181 - Qβ疫苗靶点。
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