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

摘要： 糖尿病(DM)导致脑血管功能障碍，损害海马神经发生， 导致认知能力下降。脑血管生成与神经生成结合在一起。调节细胞周期变化的分子 脑内皮细胞和神经干细胞之间的相互作用，特别是在糖尿病患者中还没有完全实现 调查过了。脑内皮细胞结构性地释放外切体，它介导细胞间 沟通。我们的初步数据表明，外切体起源于功能失调的大脑 糖尿病大鼠血管内皮细胞与神经干细胞沟通，抑制神经发生。重要的是 健康成年大鼠脑内皮细胞外切体对DM大鼠的作用 有力地改善认知功能，最大限度地减少糖尿病引起的脑血管内皮细胞功能障碍和糖尿病- 海马神经发生受损。因此，在这一应用中，我们建议开发脑内皮细胞 外切体作为糖尿病致老年大鼠认知功能减退的机制治疗。一共有三个 目标。目的1验证CE-exo治疗减少DM大鼠认知缺陷的假设。AIM 2测试 CE-exo治疗可改善脑血管的通畅性和完整性，并促进 老年糖尿病大鼠的神经发生。AIM 3测试了工程外体携带提升的假说 选择性miRNAs对脑血管功能、神经发生和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.