Cerebral endothelial cells derived exosomes as a therapy for cognitive impairment in aged diabetic rats

摘要： 糖尿病（DM）可引起脑血管功能障碍，损害海马神经发生， 导致认知能力下降脑血管新生与神经发生偶联。分子介导的 脑内皮细胞和神经干细胞之间的相互作用，特别是在糖尿病中， 研究了脑内皮细胞组成性释放外泌体，其介导细胞间 通信我们的初步数据表明，来源于功能障碍的大脑外泌体， 糖尿病大鼠内皮细胞与神经干细胞通讯，抑制神经发生。重要的是， 向DM大鼠施用从健康成年脑的脑内皮细胞分离的外来体（CE-exo） 显著改善认知功能，最大限度地减少DM诱导的脑内皮细胞功能障碍和DM， 海马神经发生受损因此，在本申请中，我们建议开发脑内皮细胞， 外泌体作为老年大鼠中DM诱导的认知下降的机制疗法。有三 目标。目的1检验CE-exo治疗减少DM大鼠的认知缺陷的假设。Aim 2测试 CE-exo治疗改善脑血管通畅性和完整性， 老年糖尿病大鼠的神经发生。目的3测试工程化的外泌体携带升高的 选择性的miRNAs对脑血管功能和神经发生以及认知功能有增强作用， 功能这些研究将为开发CE-exo作为一种创新的治疗方法提供临床前证据。 糖尿病引起的认知功能障碍

Abstract: Diabetes mellitus (DM) induces cerebral vascular dysfunction and impairs the hippocampal neurogenesis, resulting in cognitive decline. Cerebral angiogenesis couples with neurogenesis. Molecules that mediate the interaction between cerebral endothelial cells and neural stem cells in particular in DM have not been fully investigated. Cerebral endothelial cells constitutively release exosomes, which mediate intercellular communication. Our preliminary data demonstrated that exosomes derived from dysfunctional cerebral endothelial cells of DM rats communicate with neural stem cells and inhibit neurogenesis. Importantly, administration of exosomes isolated from cerebral endothelial cells (CE-exo) of healthy adult brain to DM rats robustly improved cognitive function and minimized DM-induced cerebral endothelial cell dysfunction and DM- impaired hippocampal neurogenesis. In this application, we therefore, propose to develop cerebral endothelial exosomes as a mechanism-based therapy for DM-induced cognitive decline in the aged rats. There are three Aims. Aim 1 tests the hypothesis that CE-exo treatment reduces cognitive deficits in the DM rat. Aim 2 tests the hypothesis that CE-exo treatment improves cerebral vascular patency and integrity, and promotes neurogenesis in the aged-DM rat. Aim 3 tests the hypothesis that engineered exosomes carrying elevated selective miRNAs have enhanced effects on cerebral vascular function and neurogenesis as well as cognitive function. These studies will provide preclinical evidence for developing CE-exo as an innovative treatment for DM-induced cognitive dysfunction.