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）。同样地，包括AD在内的大多数神经系统疾病也与神经系统功能障碍有关。 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CNS实质的作用受到限制。其次，实质中没有淋巴管。 我们实验室的最新发现表明，包裹大脑的脑膜含有淋巴细胞， 血管，并且该脉管系统引流间质液和脑脊液，因此， 中枢神经系统排泄物此外，与软组织不同，脑膜间隙由各种 免疫细胞的活性与大脑功能有关，包括学习和记忆。基于 根据我们的初步和已发表的结果，我们提出了一个总体假设，即与年龄有关的 脑膜炎的功能损害导致Ab的积累和聚集（并且可能 其他蛋白质），在那里触发促炎性先天免疫反应， 是认知障碍的基础如果这一假设是正确的（我们的初步数据也是如此），那么 恢复/增强通过脑膜引流可以从脑膜去除聚集物， 阻止脑膜促炎免疫，减轻AD病理和认知能力下降。我们的具体目标 将讨论：（1）脑膜炎功能的损害及其潜在机制;（2）如何 受损的脑膜炎与脑膜免疫的促炎偏斜相关;（3）是否 脑膜炎功能的恢复可以逆转局部的促炎反应， AD病理学解决这一建议的目的将揭示一个新的光对AD的发病机制和测试， 新的、未经探索的方法来缓解与认知障碍相关的认知障碍的可行性和疗效 AD.我们的方法的独特性使我们能够在疾病的过程中进行干预， 减轻症状。总而言之，我们的发现指出，迄今尚未探索的脑膜作为一个潜在的来源， AD生物标志物和治疗干预的靶点。 !