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， 降低淀粉样蛋白药物的模棱两可的试验突出了对替代解决方案的迫切需要， 预防AD。体力活动是一种容易获得的治疗方法，与> 30%的风险降低相关。 然而，身体活动，一种全身性的干预措施，如何促进大脑健康， 从根本上理解。捕捉身体活动的神经活动机制提供了一个 有机会确定新的AD治疗靶点，并完善我们对最广泛的 为大脑健康实施行为干预。这一建议建立在最近的合作基础上， Drs. Villeda和Casaletto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种新的 血液因子，糖基磷脂酰肌醇特异性磷脂酶D1（Gpld1），介导神经源性和 老年小鼠运动的记忆益处与人类的身体活动水平有关。GPLD1是一个肝脏- 从细胞表面切割GPI锚定蛋白，从而调节GPI锚定蛋白的衍生酶。 蛋白质级联。我们观察到Gpld 1不容易进入脑实质，这表明Gpld 1在脑实质中的表达是间接的。 行动方式。我们初步的小鼠和人类数据表明，系统性Gpld1降低补体和 凝血激活，调节海马血管上的GPI锚定蛋白，并与降低 血浆补体激活和脑血管完整性的更好MRI标志物。 总之，这表明Gpld1作用于免疫血管过程以支持大脑健康。鉴于早期 和AD中免疫血管功能障碍的主要参与，我们现在计划检查神经保护作用。 使用跨物种设计的血浆Gpld 1在AD中的作用。我们假设，通过免疫血管 Gpld1可能改善AD病理的神经毒性和传播，导致更慢的 病理积累和认知改善。在我们的目标中，我们将：1）测试纵向关系 血浆Gpld 1与体力活动监测（体动记录）、免疫血管和认知轨迹之间的关系 在150名老年人中进行AD连续体的研究; 2）测试全身性Gpld 1调节对免疫血管 和AD病理学小鼠模型中的神经退行性结果;和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 负调节血脑转运和增加，并与AD成人的认知呈负相关。 我们的项目定位于确定一种新型AD治疗靶点的实用性，该靶点将同时进行以下测试： 在AD病理学的啮齿动物模型中的因果途径，并评价在人类中的临床相关性。从长远来看， 这一提议将有助于我们对身体活动如何影响大脑健康的基本理解， 为一项潜在的新型AD临床试验奠定了基础。

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.