Feng Xuejian, Hou Yunyu, Liu Jiaxin, Yan Fei, Dai Mingrui, Chen Mo, Wang Jianan, Li Jie, Liu Zhenjiang, Sun Dong, Zhang Yong, Yu Xianghui, Kong Wei, Wu Hui
National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130012, China.
Changchun BCHT Biotechnology, 1260 Huoju Road, Changchun High-tech Zone, Changchun, Jilin, China.
NPJ Vaccines. 2024 Aug 20;9(1):153. doi: 10.1038/s41541-024-00942-9.
Alzheimer's disease (AD) is an intricate disorder involving amyloid deposits, neurofibrillary tangles, and chronic neuroinflammation. Though current Aβ-directed immunotherapies effectively eliminate amyloid plaques, their limited clinical benefits and notable safety concerns arise from overlooking two other neglected neurodegenerative features. Compelling evidence highlights synergistic cooperation between Aβ and tau, underscoring the imperative need to develop combinational therapies to target the diverse pathologies of AD. In this study, we present a dual AD vaccine combining Aβ and pTau vaccines, eliciting robust and enduring antibody responses against pathological Aβ and pTau in 3xTg transgenic mice. It significantly eradicated Aβ plaques and pTau tangles, suppressed neuroinflammatory factors, and markedly enhancing cognitive abilities in 3xTg mice. Mechanistically, peripheral antibodies penetrated the brain, recognizing and inhibiting Aβ and pTau aggregation, thereby reducing their cytotoxicity. In summary, this innovative multi-targeting immunotherapy remarkably ameliorates diverse AD pathologies, demonstrating maximum benefits in slowing the clinical progression of AD.
阿尔茨海默病（AD）是一种复杂的疾病，涉及淀粉样蛋白沉积、神经原纤维缠结和慢性神经炎症。尽管目前针对β淀粉样蛋白（Aβ）的免疫疗法能有效清除淀粉样斑块，但由于忽视了另外两个被忽视的神经退行性特征，其临床益处有限且存在显著的安全问题。有力证据表明Aβ与tau蛋白之间存在协同作用，这凸显了开发联合疗法以针对AD多种病理特征的迫切需求。在本研究中，我们提出了一种将Aβ疫苗和磷酸化tau蛋白（pTau）疫苗结合的双重AD疫苗，在3xTg转基因小鼠中引发了针对病理性Aβ和pTau的强大而持久的抗体反应。它显著消除了Aβ斑块和pTau缠结，抑制了神经炎症因子，并显著提高了3xTg小鼠的认知能力。从机制上讲，外周抗体穿透大脑，识别并抑制Aβ和pTau聚集，从而降低它们的细胞毒性。总之，这种创新的多靶点免疫疗法显著改善了多种AD病理特征，在减缓AD临床进展方面显示出最大益处。
