Meningeal lymphatics and immunity in Alzheimer's disease

许多神经疾病都与衰老有关，其中最突出的是阿尔茨海默氏症 疾病(AD)。同样，包括阿尔茨海默病在内的大多数神经疾病也与神经功能障碍有关。 免疫系统。中枢神经系统(CNS)生理学至少有两个独特的方面 与神经免疫相互作用有关。首先，大脑的“免疫特权”状态表明 免疫细胞对中枢神经系统实质的免疫受到限制。其次，实质内没有淋巴管。 我们实验室的最新发现表明，包裹大脑的脑膜含有淋巴管。 血管，这种血管系统排出间质和脑脊液，因此，功能 中枢神经系统引流的淋巴管。此外，与脑膜实质不同的是，脑膜间隙由不同种类的 免疫细胞，其活动与大脑功能有关，包括学习和记忆。基座 根据我们的初步和已发表的结果，我们提出了与年龄有关的总体假设 脑膜淋巴管的功能损害会导致抗体的聚集和聚集(并可能 其他蛋白质)在脑膜间隙内，触发促炎的先天免疫反应 是认知障碍的基础。如果这一假设是正确的(我们的初步数据表明是这样)，那么 通过脑膜淋巴管恢复/加强引流可以从脑膜中移除聚集体， 抑制脑膜前炎性免疫，减轻AD病理和认知功能下降。我们的具体目标 将解决：(1)脑膜淋巴功能受损及其潜在机制；(2)如何 脑膜淋巴管受损与脑膜免疫的促炎性倾斜有关；(3) 恢复脑膜淋巴功能可逆转局部促炎反应，改善炎症反应 公元病理学。解决这一提案的目的将为AD的发病机制提供新的线索，并测试 新的、未探索的方法缓解与以下疾病相关的认知障碍的可行性和有效性 广告。我们方法的独特性使我们能够在疾病过程中进行干预，从而敏锐地 缓解症状。总之，我们的发现指出，迄今未被探索的脑膜是一个潜在的来源。 阿尔茨海默病生物标志物和治疗干预的靶点。 好了！

Many neurological disorders are associated with aging, the most prominent among them being Alzheimer’s disease (AD). Likewise, majority of neurological diseases, including AD, are also associated with dysfunction of the immune system. There are at least two unique aspects of central nervous system (CNS) physiology as it relates to neuro-immune interactions. First, the ‘immune-privilege’ status of the brain suggests that access of immune cells to the CNS parenchyma is restricted. Secondly, the parenchyma is devoid of lymphatic vessels. Recent findings from our lab have demonstrated that the meninges that envelop the brain harbors lymphatic vessels, and that this vasculature drains interstitial and cerebrospinal fluids, and therefore, serves the function of CNS-draining lymphatics. Moreover, unlike the parenchyma, the meningeal spaces are populated by a variety of immune cells, the activity of which has been linked to brain function, including learning and memory. Based on our preliminary and published results, we have put forward the overarching hypothesis that the age-related functional impairment of the meningeal lymphatics results in accumulation and aggregation of Ab (and potentially other proteins) within the meningeal spaces, triggering there a pro-inflammatory innate immune response, which underlies cognitive impairment. If this hypothesis is correct (and our preliminary data suggests so), then restoration/enhancement of drainage through meningeal lymphatics may remove aggregates from the meninges, halt meningeal pro-inflammatory immunity, and alleviate AD pathology and cognitive decline. Our specific aims will address: (1) The impairment of meningeal lymphatics function and its underlying mechanism; (2) How impaired meningeal lymphatics correlate with pro-inflammatory skew of meningeal immunity; (3) Whether restoration of meningeal lymphatics function could revert the local pro-inflammatory response and ameliorate AD pathology. Addressing the aims of this proposal will shed a new light on the pathogenesis of AD and test the feasibility and efficacy of new, unexplored approaches to the alleviation of cognitive impairment associated with AD. The uniqueness of our approach allows us to intervene during the course of the disease, thereby acutely alleviating the symptoms. Altogether, our findings point to the hitherto unexplored meninges as a potential source of AD biomarkers and a target for therapeutic intervention. !