# Role of endothelium in pathogenesis of cerebral amyloid angiopathy

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $654,455

## Abstract

ABSTRACT
Sporadic cerebral amyloid angiopathy (CAA) is a small vessel disease caused by cerebrovascular deposition
of amyloid-β (Aβ). CAA frequently overlaps with Alzheimer’s disease (AD), presumably because Aβ 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 Aβ 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 (Aβ-independent) endothelial functions of β-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 Aβ 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.

## Key facts

- **NIH application ID:** 10311153
- **Project number:** 1R01AG071190-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Zvonimir S Katusic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $654,455
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10311153

## Citation

> US National Institutes of Health, RePORTER application 10311153, Role of endothelium in pathogenesis of cerebral amyloid angiopathy (1R01AG071190-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10311153. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*