Meningeal lymphatics and immunity in Alzheimer's disease

阿尔茨海默病的脑膜淋巴管和免疫

• 批准号: 9428316
• 负责人: Jonathan Kipnis
• 金额: $ 136.04万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9428316
• 关键词: Ablation; Achievement; Acute; Address; Age; Aging; Aging-Related Process; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Biological Markers; Brain; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Cognitive deficits; Data; Disease; Disease Progression; Drainage procedure; Excision; Functional disorder; Goals; Immune; Immune System and Related Disorders; Immune response; Immunity; Immunologic Surveillance; Impaired cognition; Impairment; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Innate Immune Response; Intercellular Fluid; Learning; Light; Link; Lymphatic; Lymphatic vessel; Memory; Meningeal; Meninges; Mus; Neuraxis; Neuroimmune; Operative Surgical Procedures; Organ; Pathogenesis; Pathology; Pharmacology; Phenotype; Physiology; Proteins; Publishing; Recombinant Proteins; Recruitment Activity; Research; Risk Factors; Role; Senile Plaques; Source; Technology; Testing; Therapeutic; Therapeutic Intervention; Vascular Endothelial Growth Factor C; Viral Vector; abeta accumulation; age related; aged; amyloid formation; base; cisterna magna; cognitive function; early onset; functional disability; immune activation; interest; mouse model; nervous system disorder; new therapeutic target; novel; protein aggregate; protein aggregation; reduce symptoms; response; restoration; targeted treatment

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. !

许多神经系统疾病与衰老有关，其中最突出的是阿尔茨海默氏症 疾病（AD）。同样，包括AD在内的大多数神经疾病也与功能障碍有关 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“免疫特你”状态表明， 对CNS实质的免疫细胞受到限制。其次，实质没有淋巴管。 我们实验室的最新发现表明，脑膜包裹着大脑淋巴管 血管，这种脉管系统会排出间质和脑脊液，因此可以发挥功能 淋巴细胞中心的淋巴细胞药。此外，与paranchyma不同，脑膜空间是多种多样的 免疫细胞的活性与大脑功能有关，包括学习和记忆。基于 在我们的初步和发布的结果上，我们提出了与年龄有关的总体假设 脑膜淋巴机的功能障碍会导致AB的积累和聚集 脑膜空间内的其他蛋白质），触发促炎的先天免疫反应，这是 认知障碍的基础。如果此假设正确（我们的初步数据建议），那么 通过脑膜淋巴机的恢复/增强引流可能会从脑膜中清除骨料， 停止脑膜促疾病免疫学，并减轻AD病理学和认知能力下降。我们的具体目标 将解决：（1）脑膜淋巴功能及其潜在机制的损害； （2）如何 受损的脑膜淋巴细胞与脑膜免疫的促炎性偏斜相关； （3）是否 恢复脑膜淋巴机功能可以恢复局部促炎反应并改善 广告病理学。解决该提案的目的将为AD的发病机理提供新的启示，并测试 新的，出乎意料的方法的可行性和效率，以减轻与之相关的认知障碍 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 减轻症状。总之，我们的发现指出了隐藏的意外脑膜作为潜在来源 AD生物标志物和治疗干预的靶标。 呢