Leveraging mouse and human models to investigate neuroprotective effects of blood-derived exerkines in Alzheimer's disease

摘要 阿尔茨海默病(AD)是一种无法治愈的、急剧增长的公共卫生问题。继续失败，并且 降低淀粉样蛋白药物的模棱两可的试验突显出迫切需要替代解决方案来支持衰老 大脑和预防老年痴呆症。体力活动是一种现成的治疗方法，可将患心脏病的风险降低30% 阿尔茨海默氏症；然而，体力活动是一种假定的系统性干预，如何促进大脑健康并不是 从根本上理解。捕捉体力活动的神经活动机制提供了一种 有机会确定新的AD治疗靶点，并加深我们对最广泛的 实施对大脑健康的行为干预。这项提议建立在最近两国之间的合作基础上 Villeda博士和Casaletto博士在《科学》杂志上发表了一篇论文，他们的团队在论文中发现了一本小说 血因子，糖基磷脂酰肌醇特异性磷脂酶D1(Gpld1)，介导神经源性和 运动对老年小鼠的记忆有好处，并与人类的体力活动水平有关。Gpld1是一个肝脏- 一种从细胞表面切割GPI锚定蛋白的衍生酶，从而调节GPI锚定蛋白 蛋白质层叠而成。我们观察到Gpld1不容易进入脑实质，这表明 行动模式。我们的初步小鼠和人类数据表明，系统性Gpld1降低补体和 凝血激活，调节海马区血管上的GPI锚定蛋白，并与低 健康老年人的血浆补体激活和更好的脑血管完整性MRI标记物。 总之，这表明Gpld1作用于免疫血管过程，以支持大脑健康。考虑到这么早 和免疫血管功能障碍在AD中的主要参与，我们现在计划检查神经保护 采用跨物种设计研究血浆Gpld1在AD中的作用。我们假设，通过免疫血管 机制，Gpld1可以改善AD病理的神经毒性和传播，导致速度减慢 阿尔茨海默病的病理堆积和认知改善。在我们的目标中，我们将：1)检验纵向关系 血浆Gpld1与体力活动监测、免疫血管和认知轨迹之间的关系 在150名老年AD患者中；2)测试系统性Gpld1调节对免疫血管的影响 和AD病理小鼠模型中的神经退行性结果；以及3)表征血管GPI- 锚定的Gpld1底物，组织非特异性碱性磷酸酶(TNAP/ALPL)，已被证明 阿尔茨海默病患者血脑转运呈负性调节，BE增加，与认知功能呈负相关。 我们的项目定位于确定一种新的AD治疗靶点的效用，该靶点将同时进行测试 阿尔茨海默病啮齿动物模型中的因果路径以及人类临床相关性的评估。从长远来看， 这一建议将有助于我们对体力活动如何影响大脑健康的基础理解，以及 为AD潜在的新型临床试验奠定基础。

ABSTRACT Alzheimer’s disease (AD) is an untreatable, precipitously growing public health problem. Continued failed and equivocal trials for amyloid lowering drugs highlight the urgent need for alternative solutions to support the aging brain and prevent AD. Physical activity is a readily available therapy associated with >30% reduced risk of Alzheimer’s dementia; yet, how physical activity, a putatively systemic intervention, promotes brain health is not fundamentally understood. Capturing the neurologically active mechanisms of physical activity offers an opportunity to identify novel AD treatment targets and refine our understanding of one of the most widely implemented behavioral interventions for brain health. This proposal builds on a recent collaboration between Drs. Villeda and Casaletto that culminated in a publication in Science in which their teams identified a novel blood factor, Glycosylphosphatidylinositol-Specific Phospholipase D1 (Gpld1), that mediates the neurogenic and memory benefits of exercise in aged mice and relates to physical activity levels in humans. Gpld1 is a liver- derived enzyme that cleaves GPI-anchored proteins from the cell surface, thereby regulating GPI-anchored protein cascades. We observed that Gpld1 does not readily enter the brain parenchyma, suggesting an indirect mode of action. Our preliminary mouse and human data suggest that systemic Gpld1 lowers complement and coagulation activation, regulates GPI-anchored proteins on hippocampal blood vessels, and relates to lower plasma complement activation and better MRI markers of cerebrovascular integrity in healthy older adults. Together, this suggests that Gpld1 acts on immunovascular processes to support brain health. Given the early and predominant involvement of immunovascular dysfunction in AD, we now plan to examine the neuroprotective effects of plasma Gpld1 in AD using a cross-species design. We hypothesize that, through immunovascular mechanisms, Gpld1 may ameliorate the neurotoxicity and propagation of AD pathology, resulting in slower pathology accumulation and improved cognition in AD. In our Aims, we will: 1) test the longitudinal relationships between plasma Gpld1 with physical activity monitoring (actigraphy), immunovascular, and cognitive trajectories in 150 older adults across the AD continuum; 2) test the effect of systemic Gpld1 modulation on immunovascular and neurodegenerative outcomes in a mouse model of AD pathology; and 3) characterize a vascular GPI- anchored Gpld1 substrate, tissue nonspecific alkaline phosphatase (TNAP/ALPL), that has been shown to negatively regulate blood-brain transport and be increased and inversely correlate with cognition in AD adults. Our project is positioned to identify the utility of a novel AD therapy target that will be simultaneously tested for causal pathways in rodent models of AD pathology and evaluated for clinical relevance in humans. Longer term, this proposal will both facilitate our foundational understanding of how physical activity impacts brain health, and set the stage for a potential novel clinical trial for AD.