Vascular MicroRNA-212 in CAA and Alzheimer's disease

Supplement Summary and Aims The funded grant aims to determine the role of microRNAs (miRNAs) in post- transcriptional regulation in the context of cerebrovascular dysfunction and blood-brain- barrier (BBB) disruption, particularly within Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). AD is characterized by an accumulation of amyloid-β (Aβ)

plaques and neurofibrillary tangles, with cerebrovascular dysfunction (CVD) and neuroinflammation playing key roles in the progression of the disease. In fact, most cases of AD exhibit Aβ deposition in and around cerebral blood vessels, thus presenting an additive effect to the pathology of the disease.

The BBB, composed mainly of endothelial cells (ECs), regulates the entry of circulating substances from the blood to the brain and assists in clearing harmful molecules from the brain, including oligomeric Aβ. Disruption of the BBB and the accumulation of Aβ in and around cerebral blood vessels is associated with changes in ECs, yielding a

proinflammatory phenotype and leading to apoptosis. In our preliminary data of the parent grant, we have found that miRNA-212 is decreased in ECs treated with Aβ. Previously, we have shown that Aβ treatment leads to EC apoptosis and increase in EC barrier permeability. We have shown in our preliminary data that several genes involved in EC

apoptosis contain binding sequences for miRNA-212. Our overarching goal is to test the hypothesis that Aβ promotes cerebrovascular dysfunction and BBB failure via endothelial cell miRNA-212. To achieve our goal, during this Supplement I specifically aim to accomplish the following Aims. Aim 1: measure miR-212 levels in exosomes released from ECs under the same

Aβ conditions as in Aim 1 of the Grant. The release of miRNAs via exosomes may be essential for regulation in nearby cells of the neurovascular unit and may serve as a biomarker for AD and CAA diagnosis and progression. Aim 2: assess the impact of miR- 212 downregulation and rescue on BBB permeability in neurovascular unit complex

systems. To ascertain the role of miRNA in CVD and BBB loss of function.