Vascular MicroRNA-212 in CAA and Alzheimer's disease

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Summary Pathological changes in the brain vasculature contribute to Alzheimer’s disease (AD) and AD-related dementias (ADRD). Amyloid β (Aβ)-mediated endothelial damage may lead to microbleeds, stroke, hypoxia, alterations in cerebral blood flow and malfunction of the entire neurovascular unit, contributing to cognitive impairment. Micro- RNAs (miRNAs) regulate gene expression and protein levels, bearing functions essential for cell survival and functioning in normal and stress conditions. MiRNAs are highly enriched in the brain and play critical roles in development and disease. While the vascular contributions to AD pathology are well recognized, the changes in miRNA expression in endothelial cells in the AD/ADRD brain are still mostly unexplored. We propose to assess the effect of amyloid challenge on miRNA regulation in cerebral endothelial cells, addressing the overarching hypothesis that the Aβ peptide, a known causative factor of AD, triggers endothelial miRNA alterations, the most significant being miR-212 downregulation, contributing to the blood-brain barrier (BBB) failure and neurovascular dysfunction characteristic of AD. Our specific goal is to demonstrate the hypothesis that the Aβ peptide promotes cerebrovascular dysfunction and BBB failure via endothelial miR-212. Using human primary and immortalized endothelial cells, purified cerebral vessels from transgenic mice with vascular amyloidosis, and post-mortem brain vasculature from human AD cases with vascular Aβ and pure cerebral amyloid angiopathy (CAA) cases, we aim to test the following hypotheses that: Aim 1: toxic Aβ species specifically reduce miR-212 in cerebral endothelial cells. Aim 2: MiR-212 targets modulate endothelial cell stress/death genes and pathways. Aim 3: miR-212 loss disrupts BBB function. This project will benefit from the combined expertise and collaboration of two PIs specialized respectively in vascular/endothelial dysfunction in CAA and AD and miRNA research in AD and ADRD. This study will allow us to clarify the role of specific vascular miRNAs and, by re-establishing their correct equilibrium, restore gene expression and biological networks in the cerebral vasculature. The long-term goal of the proposed research will be the development of novel miRNA-focused therapeutic strategies against neurovascular dysfunction in AD and related dementias.