The aged systemic milieu inhibits hippocampal neurogenesis and cognition through VCAM1

 描述(申请人提供)：大脑结构和功能随着年龄的增长而恶化，逐渐导致成年人的认知障碍和退行性疾病的易感性。Wyss-Coray实验室最近证明，暴露在老化的全身环境中的年轻小鼠的大脑功能-特别是神经发生(新神经元的形成)和海马体中的认知功能-受到抑制，海马体是学习和记忆的关键中心。此外，该实验室还发现，老年动物的大脑功能可以通过幼年动物的血液循环来增强。虽然来自老年和年轻血浆的全身抑制和恢复活力的因子的特性开始被阐明，但这些因子如何以及是否穿过血脑屏障(BBB)并直接作用于脑组织的问题是 抑制或促进神经发生和认知功能仍未得到回答。此外，这种影响是否通过血管系统的外周相互作用来调节仍有待阐明。考虑到全身循环因子与血管系统的脑内皮细胞(BECs)直接接触，海马区的恶化或恢复活力可能部分是由内皮细胞信号的变化所介导的。拟议的研究将检验这一假设，即老化的炎症系统环境诱导内皮细胞激活和黏附分子上调，这些黏附分子在一定程度上负责系统环境和大脑之间的沟通，导致随着年龄的增长而出现功能和认知障碍。这项建议特别关注血管细胞黏附分子1(VCAM1)，在人类衰老和幼年动物衰老的体循环抑制脑功能后，发现其在血浆中的可溶性形式显著增加。目的1通过用年轻和老年血浆处理分离的BECs，寻找转录和翻译后调节VCAM1的信号通路，以及通过老年血浆注射或连接幼年和老年动物血液循环的异慢性异种共生，直接分析暴露于老年全身环境中的幼鼠BECs的转录，以确定血浆因子上调和释放VCAM1的机制。目的2将确定VCAM1是否是老化血浆对年轻的海马神经发生和认知的有害影响所必需的。VCAM1的功能将通过中和单抗、BECs中的转基因缺失或病毒传递介导的ADAM17的过度表达(负责切割和下调VCAM1功能的酶)来系统地抑制，并仔细评估海马神经发生和认知功能。这些研究将更好地理解系统环境如何消极或积极地调节大脑功能。该项目将基础神经科学、免疫学和分子生物学与翻译研究相结合，为以脑血管系统为目标的潜在疗法铺平了道路，以此作为改善与健康老龄化和多种神经退行性疾病相关的认知衰退和血管退化的一种方式。

 DESCRIPTION (provided by applicant): Brain structure and function deteriorate with age, steadily driving cognitive impairments and susceptibility to degenerative disorders in adults. It has been recently demonstrated in the Wyss-Coray lab that brain function - specifically neurogenesis (the formation of new neurons) and cognitive function in the hippocampus, a key center for learning and memory- is inhibited in young mice exposed to an aged systemic environment. Additionally, the lab discovered that aged brain function can be enhanced through systemic circulation of young blood in aged animals. While the identity of systemic inhibitory and rejuvenating factors from aged and young plasma are beginning to be elucidated, the question of how and if these factors cross the blood brain barrier (BBB) and act directly on brain tissue to inhibit or promote neurogenesis and cognitive function remained unanswered. Additionally, whether the effects are mediated through peripheral interactions via the vasculature remains to be elucidated. Considering systemic circulating factors are in direct contact with brain endothelial cells (BECs) of the vasculature, it is possible that hippocampal deterioration or rejuvenation is mediated in part by changes in endothelial cell signaling. The proposed studies will test the hypothesis that an aged, inflammatory systemic environment induces endothelial cell activation and upregulation of adhesion molecules that are responsible, in part, for the communication between the systemic environment and the brain leading to functional and cognitive impairments with age. This proposal specifically focuses on vascular cell adhesion molecule 1 (VCAM1), whose soluble form was found to increase significantly in the blood plasma during human aging and following inhibition of brain function by aged systemic circulation in young animals. Aim 1 will determine the mechanisms underlying upregulation and shedding of VCAM1 by plasma factors, by treating isolated BECs with young and aged plasma and looking into signaling pathways that regulate VCAM1 transcriptionally and post-translationally, as well as direct transcriptional analysis of BECs from young mice exposed to the aged systemic environment through aged plasma injections or heterochronic parabiosis, in which the blood circulation of young and aged animals are conjoined. Aim 2 will determine whether VCAM1 is required for the detrimental effects of aged plasma on young hippocampal neurogenesis and cognition. VCAM1 function will be inhibited systemically via neutralizing monoclonal antibody, transgenic deletion specifically in BECs, or viral delivery-mediated Adam17 overexpression (enzyme responsible for cleavage and downregulation of VCAM1 function) following aged plasma injections into young mice, and hippocampal neurogenesis and cognitive functions carefully assessed. These studies will provide a better understanding of how the systemic environment negatively or positively regulates brain function. This project combines basic neuroscience, immunology, and molecular biology with translational research, paving the way for potential therapies that target the brain vasculature as a way to ameliorate cognitive decline and vascular degeneration associated with both healthy aging and multiple neurodegenerative diseases.