Heterochronic Blood Exchange Inhibits α?Synucleinopathy through Modulating Plasma Protein's Mediation on Pathological α?Synuclein Spreading

异时性血液交换通过调节血浆蛋白对病理性 α 突触核蛋白扩散的调节来抑制 α 突触核蛋白病

• 批准号: 10495186
• 负责人: Xiaobo Mao
• 金额: $ 45.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10495186
• 关键词: Acceleration; Accounting; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Anxiety; Automobile Driving; Autopsy; Behavioral; Blood; Brain; Brain region; Cells; Clinical; Cognition; Cognitive; Dementia; Dementia with Lewy Bodies; Development; Disease; Disease Progression; Early Diagnosis; Early treatment; Enteral; Event; Exhibits; Fibrinogen; Foundations; Gastrointestinal tract structure; Gene Activation; Genetically Engineered Mouse; Goals; Human; Impaired cognition; Impairment; Inflammation; Injections; Knockout Mice; Knowledge; Ligands; Lymphocyte Activation; Mediating; Mediation; Mediator of activation protein; Memory impairment; Mental Depression; Modeling; Molecular; Molecular Profiling; Moods; Mus; Nerve Degeneration; Nerve Fibers; Nervous system structure; Neurodegenerative Disorders; Organ; Paper; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Peripheral Nervous System; Persons; Phenotype; Plasma; Plasma Proteins; Proteins; Recombinants; Rejuvenation; Risk Factors; Role; Solid; Stereotyping; System; aged; alpha synuclein; base; clinical translation; common symptom; effective therapy; experimental study; gastrointestinal system; gut-brain axis; insight; loss of function; motor disorder; mouse model; neuroinflammation; novel; novel strategies; prevent; prion-like; protein function; receptor; synucleinopathy; therapeutic target; transcriptomics; transmission process; uptake

PROJECT SUMMARY Aging is the greatest risk factor to α-synucleinopathy, a group of neurodegenerative diseases with severe cognitive impairmentand progressive motor dysfunction and dementia, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) and half of Alzheimer's disease patients (AD). Dementia is a common symptom in α-synucleinopathies: DLB is the 2nd most common dementia after Alzheimer's disease (AD) accounting for 30% of dementia cases; Around 30% of AD cases also suffer from α-synucleinopathy resulting in a more rapid and severe cognition decline than AD alone. PD is the 2nd most common neurodegenerative disease, and greater than 50% of PD cases develop PDD. In addition to cognitive and memory dysfunctions, patients with dementia also suffer from anxiety, depression and mood swings. Although α-syn pathology is highly associated with dementia, the underlying aging-related mechanism driving the pathogenesis and contributing to their progression is not known and there is no available disease modifying therapy yet. Based on substantial postmortem analysis, Braak et al. demonstrated that α-syn pathology spreads in a stereotyped fashion from the vagus to the brain, which may initiate in the gastrointestinal tract. Particularly, nearly all the DLB and PDD cases present with α-syn pathology in the gut. Both clinical and experimental observations support that pathogenic α-syn spreading is a master trigger that drives α-synucleinopathy. In our gut-brain α-synucleinopathy (GBAS) mouse model, gut-injection of pathogenic α-synuclein (α-syn) can recapitulate α-syn pathology gut-brain spreading and cognitive impairment. In our preliminary studies, heterochronic blood exchange (HBE) from young mice inhibited pathogenic α-syn transmission and neuroinflammation in aged mice, suggesting an HBE-transferred phenotype that may effectively inhibit α-synucleinopathy. We identified lymphocyte-activation gene 3 (LAG3)1, a major receptor of pathologic α-syn transmission. To identify the mechanism underlying rejuvenation and accelerated aging event, we further identified two novel LAG3-related and aging-regulating proteins that can mediate pathogenic α-syn transmission. Our studies support the feasibility to modulate plasma levels of FGL1 and sLAG3 in aged mice by the HBE approach. To determine the underlying mechanism if FGL1 and sLAG3 in the plasma are molecular mediators essential for the inhibitory effects of HBE on α-synucleinopathy an d related cognitive impairment, we have established a rigorous and robust experimental system combining the HBE approach, the GBAS model, genetically engineered mice without these factors, and recombinant FGL1 and sLAG3 proteins, for comprehensive gain- and loss-of-function analysis. Our Central Hypothesis is to identify the underlying mechanism that HBE inhibits α-synucleinopathy and related cognitive impairment through FGL1 and sLAG3. FGL1 functions as a rejuvenation factor to inhibit pathologic α-syn spreading in the gut-brain axis and alleviate consequent neurodegeneration, neuroinflammation, and cognitive impairment. sLAG3 acts as an age-acceleration factor contributing to the pathogenesis and with antagonistic function to FGL1. Strikingly, human postmortem evidence shows that α-syn pathology is observed first in the gastrointestinal system and then spreads to the brain in a stereotyped fashion. Recently, our collaborator Dr. Dawson developed a novel Gut-Brain α-synucleinopathy (GBAS) model, a sporadic α-synucleinopathy model recapitulating pathologic α-syn spreading among multiple organs and brain regions in patients. However, it remains largely unknown how aging-associated blood-borne components modulate α-synucleinopathy. As the foundation of this project, we identified lymphocyte-activation gene 3 (LAG3), a major receptor of pathologic α-syn transmission. Our preliminary results showed that heterochronic blood exchange (HBE) from young mice can inhibit pathologic α-syn transmission to cells and inflammation in aged mice. We further identified two blood-borne aging-modulated proteins that regulate LAG3-mediated pathologic α-syn transmission. The first plasma protein fibrinogen-like protein (FGL1) as the major inhibitory ligand of LAG3, is decreased by aging and inhibits α-syn transmission. The second plasma protein sLAG3 is the soluble form of LAG3 protein, and it is increased by aging and promotes α-syn transmission. Our studies also support the feasibility to use HBE approach to modulate plasma levels of FGL1 and sLAG3 in aged mice by young blood. Our Central Hypothesis is that HBE with young blood inhibits α-synucleinopathy through two aging-associated circulatory proteins (FGL1 and sLAG3) essential for LAG3-mediated pathologic α-syn transmission. FGL1 functions as a rejuvenation factor to inhibit pathologic α-syn spreading in the gut-brain axis and consequent neurodegeneration, neuroinflammation, and behavioral deficits associated α-synucleinopathy. sLAG3 acts as an age-acceleration factor with antagonistic functions to FGL1. In specific aim 1, we propose to determine if HBE ameliorates α-synucleinopathy and related cognitive impairment by increasing aging-reduced FGL1 to inhibit pathological α-syn spreading. In specific aim 2, we propose to determine if HBE ameliorates α-synucleinopathy and related cognitive impairment by decreasing aging-induced sLAG3 to inhibit pathological α-syn spreading. Modulating plasma factors is a novel strategy to inhibit pathologic α-syn spreading and treating α-synucleinopathy and dementia. Positive results from this study will justify the development of novel α-synucleinopathy therapies based on plasma factor modulation. Novel molecular insights from this project will lay a solid foundation for the optimization and clinical translation of α-synucleinopathy therapies based on FGL1 and sLAG3 modulation.

项目概要 衰老是α-突触核蛋白病的最大危险因素，α-突触核蛋白病是一组具有严重认知障碍、进行性运动功能障碍和痴呆的神经退行性疾病，例如帕金森病（PD）、路易体痴呆（DLB）和帕金森病伴痴呆（PDD）以及一半的阿尔茨海默病（AD）患者。痴呆是 α-突触核蛋白病的常见症状：DLB 是仅次于阿尔茨海默病 (AD) 的第二大常见痴呆症，占痴呆病例的 30%；大约 30% 的 AD 病例还患有 α-突触核蛋白病，导致比单纯 AD 更快、更严重的认知能力下降。 PD 是第二常见的神经退行性疾病，超过 50% 的 PD 病例会发展为 PDD。除了认知和记忆功能障碍外，痴呆症患者还患有焦虑、抑郁和情绪波动。尽管 α-syn 病理学与痴呆症高度相关，但驱动发病机制和促进其进展的潜在衰老相关机制尚不清楚，而且尚无可用的疾病修饰疗法。基于大量的事后分析，Braak 等人。证明 α-syn 病理学以一种刻板的方式从迷走神经传播到大脑，这可能始于胃肠道。特别是，几乎所有 DLB 和 PDD 病例都存在肠道 α-syn 病理。临床和实验观察都支持致病性 α-syn 传播是驱动 α-突触核蛋白病的主要触发因素。在我们的肠脑 α-突触核蛋白病 (GBAS) 小鼠模型中，肠道注射致病性 α-突触核蛋白 (α-syn) 可以重现 α-syn 病理学肠脑扩散和认知障碍。在我们的初步研究中，年轻小鼠的异时性血液交换（HBE）抑制了老年小鼠的致病性α-syn传递和神经炎症，表明HBE转移的表型可以有效抑制α-突触核蛋白病。我们鉴定了淋巴细胞激活基因 3 (LAG3)1，它是病理性 α-syn 传递的主要受体。为了确定返老还童和加速衰老事件的机制，我们进一步鉴定了两种新型 LAG3 相关和衰老调节蛋白，它们可以介导致病性 α-syn 传递。我们的研究支持通过 HBE 方法调节老年小鼠 FGL1 和 sLAG3 血浆水平的可行性。为了确定血浆中的 FGL1 和 sLAG3 是否是 HBE 对 α-突触核蛋白病和相关认知障碍的抑制作用所必需的分子介质，我们建立了一个严格而稳健的实验系统，结合了 HBE 方法、GBAS 模型、不含这些因子的基因工程小鼠以及重组 FGL1 和 sLAG3 蛋白，以进行全面的研究。 功能获得和丧失分析。我们的中心假设是确定 HBE 通过 FGL1 和 sLAG3 抑制 α-突触核蛋白病和相关认知障碍的潜在机制。 FGL1 作为一种恢复活力因子，可抑制肠-脑轴中的病理性 α-syn 扩散，并减轻随之而来的神经退行性变、神经炎症和认知障碍。 sLAG3 作为一种年龄加速因子，有助于发病机制并具有 FGL1 的拮抗功能。引人注目的是，人类尸检证据表明，α-syn 病理首先在胃肠道系统中观察到，然后以定型方式扩散到大脑。最近，我们的合作者 Dawson 博士开发了一种新型肠脑 α-突触核蛋白病 (GBAS) 模型，这是一种散发性 α-突触核蛋白病模型，重现了患者多个器官和大脑区域之间的病理性 α-突触核蛋白病扩散。然而，与衰老相关的血液成分如何调节 α-突触核蛋白病仍然很大程度上未知。作为该项目的基础，我们鉴定了淋巴细胞激活基因 3 (LAG3)，它是病理性 α-syn 传递的主要受体。我们的初步结果表明，年轻小鼠的异时性血液交换（HBE）可以抑制病理性 α-syn 向细胞的传递和老年小鼠的炎症。我们进一步鉴定了两种血源性衰老调节蛋白，它们调节 LAG3 介导的病理性 α-syn 传递。第一个血浆蛋白纤维蛋白原样蛋白 (FGL1) 作为 LAG3 的主要抑制性配体，随着衰老而减少并抑制 α-syn 传递。第二种血浆蛋白sLAG3是LAG3蛋白的可溶形式，它随着衰老而增加，促进α-syn传递。我们的研究还支持使用 HBE 方法通过年轻血液调节老年小鼠血浆 FGL1 和 sLAG3 水平的可行性。 我们的中心假设是，年轻血液中的 HBE 通过两种与衰老相关的循环蛋白（FGL1 和 sLAG3）抑制 α-突触核蛋白病，这两种蛋白对于 LAG3 介导的病理性 α-syn 传递至关重要。 FGL1 作为一种再生因子，可抑制肠-脑轴中的病理性 α-syn 扩散，以及随之而来的神经变性、神经炎症和与 α-突触核蛋白病相关的行为缺陷。 sLAG3 作为一种衰老加速因子，具有与 FGL1 拮抗的功能。在具体目标 1 中，我们建议确定 HBE 是否通过增加衰老减少的 FGL1 来抑制病理性 α-syn 扩散，从而改善 α-突触核蛋白病和相关的认知障碍。在具体目标 2 中，我们建议确定 HBE 是否通过减少衰老诱导的 sLAG3 来抑制病理性 α-syn 扩散，从而改善 α-突触核蛋白病和相关的认知障碍。调节血浆因子是抑制病理性 α-syn 扩散和治疗 α-突触核蛋白病和痴呆的新策略。这项研究的积极结果将证明基于血浆因子调节的新型 α-突触核蛋白病疗法的开发是合理的。该项目的新颖分子见解将为基于 FGL1 和 sLAG3 调节的 α-突触核蛋白病疗法的优化和临床转化奠定坚实的基础。