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

项目摘要 衰老在分子和细胞水平上改变了成年人的大脑，导致认知障碍， 增加对神经退行性疾病的易感性，例如阿尔茨海默病。我们的实验室和其他实验室 表明广泛的系统操作，如异时共生，年轻的血浆和运动， 血浆给药可改善老年小鼠的学习记忆认知功能。总的来说，这些 研究结果提出了令人兴奋的可能性，即系统因素可以恢复衰老中的大脑功能， 应用于退行性疾病，包括阿尔茨海默病。我们的实验室最近描述了一种肝脏- 脑轴，其中施用来自自愿运动小鼠的血浆发挥有益的 对老年海马的影响，部分是通过肝源性循环血液因子。我们尤其 已鉴定的糖基磷脂酰肌醇特异性磷脂酶D1（Gpld 1）-一种切割GPI的血浆酶- 来自细胞表面的锚定蛋白（GPI-AP）-作为老年人运动诱导的肝源性血液因子 老鼠和活跃的老年人。选择性增加全身Gpld 1足以恢复学习， 老年小鼠海马的记忆认知功能。虽然这些令人兴奋的发现支持了一种潜在的 尽管系统性Gpld 1在衰老中的治疗作用，但其细胞和分子靶点在很大程度上仍然是难以捉摸的。 令人惊讶的是，我们的研究结果表明，Gpld 1不容易进入大脑，这表明了一种间接的机制， 的行动。有趣的是，GPI-AP在内皮细胞上富集，这增加了Gpld 1可能在内皮细胞中起作用的可能性。 对大脑血管系统的影响，以提高老年大脑的认知能力。事实上，我的初步数据表明， 系统性Gpld 1恢复GPI锚定的磷酸酶ALPL的表达，ALPL是血管功能的调节因子， 老年小鼠海马血管中的水平更年轻。这项拟议研究的目的是 研究全身性Gpld 1对脑血管的影响，作为其对老年人有益的关键介质 个脑袋我假设靶向血管GPI锚定的Gpld 1底物可以改善年龄相关的血管病变， 功能障碍并恢复老年海马体的认知功能。这将与两个调查 具体目的：1）探讨老年人全身性Gpld 1增加对血管功能障碍的影响 海马体。2)确定靶向GPI锚定的Gpld 1底物ALPL在 老年海马体的认知功能。最终，这些研究将具有重大的转化潜力， 鉴定Gpld 1下游的分子和细胞机制作为对抗 大脑老化中的认知障碍和与衰老相关的神经退行性疾病，包括 老年痴呆症

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.