Role of endothelium in pathogenesis of cerebral amyloid angiopathy

Project: Research project

Project Details

Description

ABSTRACT Sporadic cerebral amyloid angiopathy (CAA) is a small vessel disease caused by cerebrovascular deposition of amyloid-? (A?). CAA frequently overlaps with Alzheimer?s disease (AD), presumably because A? is considered major culprit in development of AD pathology. Importantly, there is no disease-specific treatment available to patients with CAA. Relevant to this project, molecular mechanisms underlying pathogenesis of CAA are incompletely understood thereby limiting our ability to prevent initiation and progression of this disease. Despite mechanistic differences between vascular-induced brain injury in CAA and neurodegenerative injury in AD, clinically, CAA overlaps with AD and it is associated with more severe cognitive impairment in AD patients. This application is designed to advance the concept that in early stages of CAA, deposition of endothelium-derived A? in cerebral blood vessel wall is an important mechanism contributing to pathogenesis of the disease. We performed extensive preliminary studies on cultured human brain microvascular endothelial cells (BMECs), mouse microvessels, and brain endothelial cells isolated by fluorescence activated cell sorting (FACS). Next generation sequencing (RNA-Seq) was used to determine global gene expression profiles in human and murine cerebrovascular endothelium. Genetically modified mice and a murine experimental model of CAA were used to validate and expand observations obtained in cultured human endothelium. We identified previously unrecognized (A?-independent) endothelial functions of ?-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) and its homologue (BACE2). Consistency between findings in human and murine endothelium was in agreement with strong evolutionary conservation of BACE1 and BACE2. However, while endothelial BACE1 exerts detrimental vascular effects, endothelial BACE2 appears to be previously unrecognized and very important vascular protective molecule. Further preliminary analyses of BACE1 and BACE2 function and signaling in endothelium of mice vulnerable to development of CAA, suggested that dysfunctional BACE1 and BACE2 in endothelium promote elevated A? deposition in the cerebral blood vessels. Based on these preliminary findings our working hypothesis is that endothelial BACE1 and BACE2 play distinct roles in cerebrovascular homeostasis and pathogenesis of CAA. We anticipate that successful completion of this project will offer new opportunities to utilize endothelial BACE1 and BACE2 as molecular targets for therapeutic interventions designed to prevent detrimental effects of CAA on cerebrovascular and cognitive function.
StatusActive
Effective start/end date9/1/216/30/22

Funding

  • National Institute on Aging: $654,455.00

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