Investigating the role of the exercise blood factor Gpld1 in restoring brain vasculature function and cognition in aging

研究运动血因子 Gpld1 在恢复脑血管功能和衰老认知中的作用

基本信息

批准号：
10607225
负责人：
Gregor Bieri
金额：
$ 7.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607225
关键词：
Adult Age Age-associated memory impairment Aging Alzheimer&apos s Disease Animals Automobile Driving Blood Blood Vessels Brain Cardiovascular system Cell Nucleus Cell Surface Proteins Cerebrovascular system Cognition Cognitive Confocal Microscopy Data Degenerative Disorder Dementia Disease Elderly Endothelial Cells Enzymes Exercise GPI Membrane Anchors Glycosylphosphatidylinositols Hippocampus Human Immunohistochemistry Impaired cognition Impairment Label Learning Liver Measures Mediator Memory Molecular Molecular Target Mus Neurodegenerative Disorders Parabiosis Patients Permeability Phosphoric Monoester Hydrolases Physical Exercise Plasma Plasma Proteins Predisposition Proteins Proteolysis Radial Rejuvenation Research Role Testing Therapeutic Tracer Vascular Cognitive Impairment Vascular Diseases age related age related neurodegeneration aged aging brain aging hippocampus aging population arm brain dysfunction brain parenchyma cellular targeting cognitive function fitness hippocampal atrophy improved inhibitor interest mouse model new therapeutic target novel novel therapeutics object recognition phospholipase D1 single nucleus RNA-sequencing spatial memory systemic intervention theories transcytosis translational potential water maze

项目摘要

PROJECT SUMMARY Aging changes the adult brain at the molecular and cellular levels, driving cognitive impairments and drastically increasing susceptibility to neurodegenerative diseases, such as Alzheimer’s disease. Our lab, and others, have shown that broad systemic manipulations, such as heterochronic parabiosis, young blood plasma and exercise plasma administration can improve learning and memory cognitive functions in aged mice. Collectively, these findings raise the exciting possibility for systemic factors to restore brain function in aging with potential applications for degenerative conditions, including Alzheimer’s disease. Our lab recently described a liver-to- brain axis, in which administration of blood plasma derived from voluntary exercised mice exerts beneficial effects on the aged hippocampus, in part, through liver-derived circulating blood factors. In particular, we identified Glycosylphosphatidylinositol Specific Phospholipase D1 (Gpld1) – a plasma enzyme that cleaves GPI- anchored proteins (GPI-AP) from the cell surface – as an exercise-induced, liver-derived blood factor in aged mice and active elderly humans. Selectively increasing systemic Gpld1 was sufficient to restore learning and memory cognitive functions in the hippocampus of aged mice. While these exciting findings support a potential therapeutic role for systemic Gpld1 in aging, its cellular and molecular targets remain largely elusive. Surprisingly, our findings indicate that Gpld1 does not readily enter the brain, suggesting an indirect mechanism of action. Interestingly, GPI-APs are enriched on endothelial cells, raising the possibility that Gpld1 may be acting on the brain vasculature to improve cognition in the aged brain. Indeed, my preliminary data indicate that systemic Gpld1 restores expression of the GPI-anchored phosphatase ALPL, a regulator of vascular function, to more youthful levels on hippocampal blood vessels of aged mice. The purpose of this proposed study is to investigate the effect of systemic Gpld1 on the brain vasculature, as a critical mediator of its benefits on the aged brain. I hypothesize that targeting vascular GPI-anchored Gpld1 substrates ameliorates age-related vascular dysfunction and rejuvenates cognitive function in the aged hippocampus. This will be investigated with two Specific Aims: 1) Investigate the effects of increasing systemic Gpld1 on vascular dysfunction in the aged hippocampus. 2) Determine the rejuvenating potential of targeting the GPI-anchored Gpld1 substrate ALPL on cognitive function in the aged hippocampus. Ultimately, these studies will have significant translational potential, identifying molecular and cellular mechanisms downstream of Gpld1 as novel therapeutic targets to counter cognitive impairments in the aging brain and aging-associated neurodegenerative diseases, including Alzheimer’s disease.

项目概要衰老会在分子和细胞水平上改变成人大脑，导致认知障碍和戏剧性的后果。我们的实验室和其他实验室发现，人们对神经退行性疾病（例如阿尔茨海默病）的易感性增加。研究表明，广泛的系统性操作，例如异时性联体共生、年轻血浆和运动总的来说，血浆给药可以改善老年小鼠的学习和记忆认知功能。研究结果提出了系统性因素在衰老过程中恢复大脑功能的令人兴奋的可能性我们的实验室最近描述了一种从肝脏到退化性疾病的应用。脑轴，其中来自自愿运动的小鼠的血浆的施用发挥有益作用对衰老海马体的影响部分是通过肝源性循环血液因子实现的。鉴定出糖基磷脂酰肌醇特异性磷脂酶 D1 (Gpld1)——一种裂解 GPI 的血浆酶来自细胞表面的锚定蛋白（GPI-AP）——作为老年人运动诱发的肝源性血液因子选择性增加全身性 Gpld1 足以恢复小鼠和活跃的老年人的学习和能力。老年小鼠海马体的记忆认知功能虽然这些令人兴奋的发现支持了潜在的潜力。全身性 Gpld1 在衰老过程中的治疗作用、其细胞和分子靶点仍然很大程度上难以捉摸。令人惊讶的是，我们的研究结果表明 Gpld1 不容易进入大脑，这表明存在间接机制提示，GPI-AP 在内皮细胞上富集，增加了 Gpld1 发挥作用的可能性。事实上，我的初步数据表明，全身性 Gpld1 恢复 GPI 锚定磷酸酶 ALPL（血管功能调节剂）的表达，老年小鼠海马血管中的水平更年轻。这项研究的目的是研究全身性 Gpld1 对脑血管系统的影响，作为其对老年人益处的关键介质我认为靶向血管 GPI 锚定的 Gpld1 底物可以改善与年龄相关的血管。老年海马体功能障碍和恢复认知功能这将通过两个研究进行研究。具体目标：1）研究增加全身性Gpld1对老年人血管功能障碍的影响 2) 确定针对 GPI 锚定的 Gpld1 底物 ALPL 的恢复潜力。最终，这些研究将具有重大的转化潜力，确定 Gpld1 下游的分子和细胞机制作为新的治疗靶点衰老大脑的认知障碍和与衰老相关的神经退行性疾病，包括阿尔茨海默病。