Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Nature. 2021 May;593(7858):255-260. doi: 10.1038/s41586-021-03489-0. Epub 2021 Apr 28.
Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
阿尔茨海默病（AD）是痴呆症最常见的病因。虽然目前尚无有效的 AD 治疗方法，但针对淀粉样蛋白β（Aβ）的单克隆抗体的被动免疫疗法是一种很有前途的治疗策略。脑膜淋巴管引流在 Aβ在大脑中的积累中起着重要作用，但尚不清楚调节脑膜淋巴管功能是否会影响 AD 免疫治疗的结果。在这里，我们发现 5xFAD 小鼠（一种表达家族性 AD 中发现的五种突变的淀粉样沉积小鼠模型）脑膜淋巴管的消融通过加剧 Aβ的沉积、小胶质细胞增生、神经血管功能障碍和行为缺陷，使接受抗 Aβ被动免疫治疗的小鼠的预后恶化。相比之下，血管内皮生长因子 C 的治疗性传递可改善单克隆抗体对 Aβ的清除。值得注意的是，功能受损的脑膜淋巴管 5xFAD 小鼠的小胶质细胞的基因特征与 AD 患者大脑中激活的小胶质细胞的转录谱之间存在很大的重叠。总体而言，我们的数据表明，脑膜淋巴管引流功能受损会加剧 AD 中的小胶质细胞炎症反应，而增强脑膜淋巴管功能并结合免疫疗法可能会带来更好的临床效果。
