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

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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.