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

利用小鼠和人类模型研究血液来源的运动因子对阿尔茨海默病的神经保护作用

• 批准号: 10901031
• 负责人: Kaitlin B Casaletto
• 金额: $ 119.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901031
• 关键词: Acceleration; Adult; Aging; Alkaline Phosphatase; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Animals; Behavior Therapy; Behavioral Paradigm; Biochemical; Biological; Biological Markers; Blood; Blood Vessels; Blood brain barrier dysfunction; Brain; Cell Nucleus; Cell Surface Proteins; Clinical Trials; Coagulation Process; Cognition; Cognitive; Collaborations; Collection; Complement; Complement Activation; Confocal Microscopy; Data; Dementia; Elderly; Endothelium; Enzymes; Etiology; Evaluation; Exercise; Functional disorder; GPI Membrane Anchors; Glycosylphosphatidylinositols; Hippocampus; Human; Human Resources; Immunohistochemistry; Impaired cognition; Impairment; Label; Learning; Liver; Magnetic Resonance Imaging; Measures; Mediating; Memory; Monitor; Mus; Nerve Degeneration; Neurologic; Neurons; Outcome; Pathology; Pathway interactions; Permeability; Pharmaceutical Preparations; Physical activity; Plasma; Plasma Proteins; Positioning Attribute; Process; Proteins; Public Health; Publications; Regulation; Research; Research Institute; Rodent Model; Science; Symptoms; Testing; Tissues; Tracer; Vascular Diseases; actigraphy; aged; aging brain; animal resource; brain health; brain magnetic resonance imaging; brain parenchyma; cerebrovascular; clinically relevant; cognitive benefits; dementia risk; design; human data; human model; improved; inhibitor; magnetic resonance imaging biomarker; mouse model; neurobehavioral; neurodegenerative phenotype; neurogenesis; neuroinflammation; neuroprotection; neurotoxicity; new therapeutic target; novel; phospholipase D1; prevent; systemic intervention; targeted treatment

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.

抽象的 阿尔茨海默氏病（AD）是一个无法治愈、急剧增长的公共卫生问题，且持续失败。 降低淀粉样蛋白药物的模棱两可的试验凸显了迫切需要替代解决方案来支持衰老 体力活动是一种现成的疗法，可将患 AD 的风险降低 30% 以上。 阿尔茨海默氏痴呆症；然而，身体活动（一种假定的系统性干预措施）如何促进大脑健康却并不明确。 从根本上理解身体活动的神经活动机制提供了一种方法。 有机会确定新的 AD 治疗目标并加深我们对最广泛的治疗目标之一的理解 该提案建立在最近合作的基础上。 维莱达博士和卡萨莱托博士最终在《科学》杂志上发表了一篇论文，其中他们的团队发现了一部小说 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 运动对老年小鼠的记忆力有好处，并且与人类的体力活动水平有关。 衍生酶从细胞表面裂解 GPI 锚定蛋白，从而调节 GPI 锚定蛋白 我们观察到 Gpld1 不容易进入脑实质，这表明存在间接的作用。 我们的初步小鼠和人类数据表明，全身性 Gpld1 会降低补体和 凝血激活，调节海马血管上的 GPI 锚定蛋白，并与较低的 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。 总之，这表明 Gpld1 作用于免疫血管过程以支持大脑健康。 以及 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 我们使用跨物种设计通过免疫血管研究了血浆 Gpld1 对 AD 的影响。 Gpld1 可能会改善 AD 病理的神经毒性和传播，从而减慢 AD 中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 Gpld1 与体力活动监测（体动记录仪）、免疫血管和认知轨迹之间的关系 在 150 名患有 AD 连续体的老年人中进行测试；2) 测试全身性 Gpld1 调节对免疫血管的影响； AD 病理学小鼠模型中的神经退行性结果；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 负向调节血脑运输并增加，并与 AD 成人的认知呈负相关。 我们的项目旨在确定一种新型 AD 治疗靶点的效用，该靶点将同时进行测试 AD 病理学啮齿动物模型的因果路径以及人类临床相关性的评估。 该提案将促进我们对身体活动如何影响大脑健康的基本了解，并且 为 AD 潜在的新型临床试验奠定了基础。