Immunomodulatory Roles of Amyloid-Beta and Amyloid Precursor Protein in CNS Autoi

描述（由申请人提供）：多发性硬化症（MS）是一种由外周T淋巴细胞浸润和攻击中枢神经系统（CNS）介导的自身免疫性疾病。了解在多发性硬化和中枢神经系统自身免疫过程中介导中枢神经系统和免疫系统之间串扰的重要蛋白调节因子对开发治疗药物至关重要。本研究的目的是研究淀粉样蛋白前体蛋白（APP）及其代谢衍生物淀粉样蛋白-¿-42 （A¿42）如何调节中枢神经系统自身免疫和一般免疫细胞功能。我们的实验室最近在复发缓解型MS （RRMS）患者的脑脊液中发现了A¿42表位作为适应性免疫反应的靶标。使用实验性自身免疫性脑脊髓炎（EAE），一种多发性硬化症的动物模型，我发现体内给药A¿42可以减轻上行性麻痹，减少脑和脊髓的炎症病变，并抑制外周免疫细胞的激活。此外，在缺乏APP表达的小鼠模型中，EAE诱导导致了剧烈的死亡率和非典型EAE疾病进展特征的行为症状。组织学特征未见中枢神经系统炎症，提示死亡原因发生在中枢神经系统外。本研究旨在通过研究APP在炎症的先天和适应性成分中的功能必要性以及A¿42抑制免疫细胞功能的机制来扩展这些初步发现。为了实现这些目标，我将使用体内和体外研究，包括分子和细胞免疫学分析，探索A¿42和APP对主动和被动EAE诱导的影响，以及用A¿42和APP调节后CNS组织的组织学表征。这些研究将阐明A¿42和APP作为有益肽的新颖和矛盾的作用，可以减弱对CNS的外周免疫。

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is an autoimmune disorder mediated by peripheral T lymphocytes that infiltrate and attack the central nervous system (CNS). Understanding important protein regulators that mediate crosstalk between the CNS and immune system during MS and CNS autoimmunity is critical towards developing therapeutic agents. The goal of this proposal is to investigate how amyloid precursor protein (APP) and its metabolic derivative, amyloid-¿-42 (A¿42), regulate CNS autoimmunity and general immune cell function. Our laboratory has recently identified an epitope of A¿42 as a target of adaptive immune responses in the cerebrospinal fluid of relapsing remitting MS (RRMS) patients. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, I have found that in vivo administration of A¿42 attenuates ascending paralysis, reduces inflammatory lesions in the brain and spinal cord, and suppresses peripheral immune cell activation. Furthermore, in a mouse model lacking APP expression, EAE induction resulted in drastic mortality and behavioral symptoms uncharacteristic of classic EAE disease progression. No CNS inflammation was observed by histological characterization, indicating that the cause of death occurred outside of the CNS. This proposal seeks to extend these initial findings by investigating both the functional necessity of APP in innate and adaptive components of inflammation and the mechanisms by which A¿42 suppresses immune cell function. Towards these goals, I will use in vivo and in vitro studies including molecular and cellular immunological assays, exploration of the effects of A¿42 and APP on active and passive EAE induction, and histological characterization of CNS tissue after modulation with A¿42 and APP. These studies will illuminate a novel and paradoxical role for A¿42 and APP as beneficial peptides that attenuate peripheral immunity against the CNS. ) PUBLIC HEALTH RELEVANCE: Multiple Sclerosis (MS) is a devastating inflammatory disorder of the central nervous system that affects 1 out of every 700 people annually in the US. The research described here focuses on amyloid-2 and its precursor protein, APP, as critical modulators of autoimmunity that can attenuate inflammation in diseases like MS. The proposed research will provide insights on pathological mechanisms of MS and explore potential therapeutics that could improve the quality of life for those who suffer from the disease.