Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease.
Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease.
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DOI：
10.1038/s41586-018-0368-8
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发表时间：
2018-08
期刊：
影响因子：
64.8
通讯作者：
Kipnis J
中科院分区：
文献类型：
--
作者：
Da Mesquita S;Louveau A;Vaccari A;Smirnov I;Cornelison RC;Kingsmore KM;Contarino C;Onengut-Gumuscu S;Farber E;Raper D;Viar KE;Powell RD;Baker W;Dabhi N;Bai R;Cao R;Hu S;Rich SS;Munson JM;Lopes MB;Overall CC;Acton ST;Kipnis J
衰老是许多神经系统疾病的主要危险因素，脑衰老的机制仍然难以捉摸。与其他组织不同，中枢神经系统（CNS）实质缺乏淋巴管系统，废物的清除主要通过血管旁途径进行。脑膜淋巴管的（重新）发现和表征促使评估其在CNS废物清除中的作用。在这里，我们表明，脑膜炎引流大分子从中枢神经系统（CSF和ISF）到颈部淋巴结。脑膜淋巴功能受损会减缓CSF大分子的血管旁流入和ISF大分子的流出，并诱导认知障碍。用血管内皮生长因子C治疗老年小鼠可增强CSF大分子的脑膜淋巴引流，改善脑灌注和学习记忆能力。阿尔茨海默病（AD）转基因小鼠模型中脑膜淋巴管的破坏促进脑膜中的淀粉样蛋白沉积，这与人类脑膜病理学非常相似，并加速实质淀粉样蛋白积累。我们的研究结果表明，脑膜淋巴功能障碍可能是AD病理学和与年龄相关的认知能力下降的一个加重因素。因此，脑膜淋巴功能的增强可能是预防或延缓年龄相关性神经系统疾病的一个有前途的治疗靶点。
Aging is a major risk factor for many neurological pathologies and the mechanisms underlying brain aging remain elusive. Unlike other tissues, the central nervous system (CNS) parenchyma is devoid of lymphatic vasculature and removal of waste products is performed mainly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels prompted for an assessment of their role in CNS waste clearance. Here we show that meningeal lymphatics are draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes. Impairment of meningeal lymphatic function slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment. Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer’s disease (AD) promotes amyloid deposition in the meninges, which closely resembles human meningeal pathology, and aggravates parenchymal amyloid accumulation. Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
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