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

摘要： 糖尿病（DM）引起脑血管功能障碍并损害海马神经发生， 导致认知能力下降。脑血管生成与神经发生耦合。介导的分子 脑内皮细胞和神经干细胞之间的相互作用，特别是在 DM 中的相互作用尚未完全阐明 调查了。脑内皮细胞组成性释放外泌体，介导细胞间相互作用 沟通。我们的初步数据表明，外泌体源自功能失调的大脑 DM 大鼠的内皮细胞与神经干细胞通讯并抑制神经发生。重要的是， 将从健康成年大脑的脑内皮细胞（CE-exo）分离的外泌体给予DM大鼠 显着改善认知功能并最大限度地减少 DM 引起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 外泌体作为一种基于机制的疗法，治疗糖尿病引起的老年大鼠认知能力下降。有三个 目标。目标 1 检验 CE-exo 治疗可减少 DM 大鼠认知缺陷的假设。目标 2 测试 CE-exo 治疗改善脑血管通畅性和完整性的假设，并促进 老年糖尿病大鼠的神经发生。目标 3 检验了工程外泌体携带升高的假设 选择性 miRNA 对脑血管功能、神经发生以及认知能力具有增强作用 功能。这些研究将为开发 CE-exo 作为创新治疗方法提供临床前证据 DM 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.