TITLE: Deciphering angiopoietin-2 regulation of BBB disruption and neuroinflammation in Alzheimer’s disease PROJECT SUMMARY Alzheimer’s disease (AD) is a fatal neurodegenerative disorder with limited therapeutic options thus necessitating the urgency to identify new drug targets for improved treatments. Increasing evidence has suggested that neuroinflammation contributes to and drives AD pathogenesis. In this context, the age-related disruption of blood–brain barrier (BBB), a protective and highly specialized endothelial cell membrane in the brain, can promote inflammatory processes. Therefore, identifying the molecular determinants of BBB disruption and neuroinflammation in aging, which can contribute to AD progression, is necessary to guide the identification of new therapeutic targets and potential biomarkers. Previous work has shown that the signaling molecule angiopoietin-2 (Ang2), which binds to the receptor tyrosine kinase Tie2 in endothelial cells, is a potent driver of vascular destabilization. Our previous work has demonstrated that under inflammatory conditions, Ang2 function switches from a Tie2 agonist to a Tie2 antagonist to promote vascular destabilization and leakage. However, the contribution of the Ang2/Tie2 signaling pathway to BBB disruption and neuroinflammatory processes in aging and AD progression is largely unknown. Our preliminary evidence shows that ANGPT2 (Ang2) levels are increased in the human late-stage AD brain as well as in brains of AD transgenic mice (5xFAD). Furthermore, we found that this Ang2 increase correlates with fibrinogen deposition and impaired pericyte coverage, both indicative of BBB disruption and associated with AD pathology. We will use mouse models of AD as well as human AD brain tissue and blood specimens from AD patients to determine the contribution of the Ang2/Tie2 pathway to BBB disruption in AD. In Aim 1, we will determine the involvement of Ang2/Tie2 signaling in the process of BBB disruption and neuroinflammation during aging. Studies will assess differences in Ang2/Tie2 signaling, BBB integrity, vascular leakage, and fibrinogen deposition in aging mice. Additionally, genetic gain- and loss-of-function strategies will be used to determine the significance of Ang2/Tie2 signaling in BBB integrity and neuroinflammation in these mice. In Aim 2, we will determine the significance of Ang2/Tie2 signaling in the regulation of BBB integrity and neuroinflammation during AD progression. Studies in AD mouse models combined with genetic approach will identify the significance of Ang2/Tie2 signaling in promoting BBB disruption, neuroinflammatory progression, and AD pathogenesis. Additionally, studies using human AD brain and blood specimens will determine if alterations in Ang2/Tie2 signaling are associated with BBB disruption, fibrinogen deposition, and AD pathology. Successful completion of this project will increase our basic understanding of novel regulators of neurovascular dysfunction and neuroinf...