Stem Cell-Derived Exosomes, MrgD and Vascular Cognitive Impairment in Aging Abstract Cerebrovascular dysfunction in aging increases risk for the development of cognitive decline and Alzheimer’s disease. Adult hematopoietic stem/progenitor cells (HSCs) play an important role in maintaining vascular homeostasis. Our novel preliminary studies identified that exosomes, nanovesicles, derived from HSCs of Older subjects (Old-HSC-Exos) induced dysfunction the human brain microvascular endothelial cells (BMECs) characterized by impaired mitochondrial bioenergetics and attenuated angiogenesis. In agreement with these findings, brain microvessels (BMVs) from Old mice showed imbalance in mitochondrial bioenergetics compared to the Young- BMVs. Furthermore, we have discovered that activation of Mas-related G-protein coupled receptor, D (MrgD) reversed age-associated impairment in bioenergetics in BMVs. This proposal tests the hypothesis that HSC-derived exosomes from Older individuals induce imbalance in the mitochondrial bioenergetics and impair cerebrovascular function resulting in cognitive decline. We further hypothesize that activation of MrgD is novel pharmacological approach for the treatment of vascular dementia. We will evaluate molecular cargo in the exosomes derived from Young and Old individuals by RNAseq analysis and determine the mitochondrial functions of selected molecules in the brain MVECs and BMVs. The potential of Mrgd activator Alamandine in reversing the detrimental effects of Old-HSC-Exos in the endothelial mitochondria and BMVs. We’ll determine the detrimental effects of Old-HSC-Exos in murine BMVs and test their potential to induce vascular dementia and cognitive decline in the Young and Old mice. The potential benefits of MrgD activators in Old-HSC-Exos-induced vascular dementia will be evaluated in vivo. Lastly, pharmacology of MrgD activators will be evaluated in APP/PS1 mice. If carried out successfully, this proposal will provide proof-of-concept for a novel role of HSC-exosomes in the pathology of vascular dementia and for MrgD as a promising target for the treatment.

Stem Cell-Derived Exosomes, MrgD and Vascular Cognitive Impairment in Aging Narrative This proposal tests a novel hypothesis that in aging individuals stem cells interact with blood vessels in the brain via secreting nanovescilces and induce dysfunction, which eventually causes cognitive decline. The proposal furthermore tests if a peptide called Alamandine can reverse dysfunctions induced by aging stem cells and prevent cognitive decline. If carried out successfully, this proposal will provide proof-of-concept for a novel therapeutic target for the treatment of aging- associated cognitive decline.