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病 疾病（AD）。同样，大多数神经系统疾病，包括 AD，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“免疫特权”状态表明， 中枢神经系统实质的免疫细胞受到限制。其次，实质上没有淋巴管。 我们实验室的最新研究结果表明，包围大脑的脑膜蕴藏着淋巴管 血管，并且该脉管系统排出间质液和脑脊液，因此具有以下功能 中枢神经系统引流淋巴管。此外，与实质不同，脑膜空间充满了各种 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，即与年龄相关的 脑膜淋巴管的功能损伤导致抗体的积累和聚集（并可能 其他蛋白质）在脑膜腔内，触发促炎先天免疫反应， 是认知障碍的基础。如果这个假设是正确的（我们的初步数据表明如此），那么 恢复/增强通过脑膜淋巴管的引流可以去除脑膜中的聚集物， 停止脑膜促炎免疫，缓解 AD 病理和认知能力下降。我们的具体目标 将解决：（1）脑膜淋巴管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偏差相关； (3) 是否 脑膜淋巴管功能的恢复可以恢复局部促炎症反应并改善 AD病理学。解决该提案的目标将为 AD 的发病机制提供新的线索并测试 缓解与认知障碍相关的新的、未经探索的方法的可行性和有效性 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，从而迅速 缓解症状。总而言之，我们的研究结果表明迄今为止尚未探索的脑膜是一个潜在的来源 AD 生物标志物和治疗干预的目标。 ！