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

项目总结 衰老在分子和细胞水平上改变成年人的大脑，导致认知障碍，并极大地 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都有 表明广泛的系统性操作，如异慢性异种共生、年轻血浆和运动 血浆给药可改善老龄小鼠的学习记忆认知功能。总而言之，这些 这一发现提高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，具有潜力 应用于包括阿尔茨海默病在内的退行性疾病。我们的实验室最近描述了一种肝脏到- 脑轴，在其中给予来自自愿锻炼的小鼠的血浆起到有益的作用 对衰老的海马体的影响，部分是通过肝脏衍生的循环血液因子。特别是，我们 鉴定出糖基化磷脂酰肌醇特异性磷脂酶D1(Gpld1)-一种裂解GPI的血浆酶- 细胞表面锚定蛋白(GPI-AP)--老年人运动诱导的肝源性血液因子 老鼠和活跃的老年人类。选择性地增加全身Gpld1足以恢复学习和 老年小鼠海马区的记忆认知功能。虽然这些令人兴奋的发现支持一种潜在的 系统Gpld1在衰老中的治疗作用，其细胞和分子靶点在很大程度上仍然难以捉摸。 令人惊讶的是，我们的发现表明Gpld1并不容易进入大脑，这表明这是一种间接的机制 行动的一部分。有趣的是，GPI-AP在内皮细胞上富含，增加了Gpld1可能起作用的可能性 对脑血管系统的研究，以改善老年大脑的认知能力。事实上，我的初步数据表明 系统性Gpld1恢复血管功能调节因子GPI锚定的磷酸酶ALPL的表达 老龄小鼠海马区血管的年轻化水平。这项拟议研究的目的是 研究系统性Gpld1对脑血管系统的影响，作为其对老年人益处的关键中介 大脑。我假设靶向血管GPI锚定的Gpld1底物可以改善与年龄相关的血管 使老年海马体的认知功能障碍和恢复活力。这将与两个人一起调查 具体目的：1)研究系统性Gpld1升高对老年人血管功能障碍的影响 海马体。2)确定靶向GPI锚定的Gpld1底物ALPL的复壮潜力 老年海马体的认知功能。最终，这些研究将具有巨大的翻译潜力， 识别Gpld1下游的分子和细胞机制作为新的治疗靶点 衰老大脑中的认知障碍和与衰老相关的神经退行性疾病，包括 阿尔茨海默氏症。

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.