BACE2 Deficiency Impairs Expression and Function of Endothelial Nitric Oxide Synthase in Brain Endothelial Cells

Overview

Journal J Neurochem

Specialties Chemistry
Neurology

Date 2023 Aug 7

PMID 37547981

Authors

Tongrong He

Livius V Duscio

Zvonimir S Katusic

Affiliations

Soon will be listed here.

Abstract

Beta-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) is highly expressed in cerebrovascular endothelium. Notably, BACE2 is one of the most downregulated genes in cerebrovascular endothelium derived from patients with Alzheimer's disease. The present study was designed to determine the role of BACE2 in control of expression and function of endothelial nitric oxide synthase (eNOS). Genetic downregulation of BACE2 with small interfering RNA (BACE2siRNA) in human brain microvascular endothelial cells (BMECs) significantly decreased expression of eNOS and elevated levels of eNOS phosphorylated at threonine residue Thr495, thus leading to reduced production of nitric oxide (NO). BACE2siRNA also suppressed expression of APP and decreased production and release of soluble APPα (sAPPα). In contrast, adenovirus-mediated overexpression of APP increased expression of eNOS. Consistent with these observations, nanomolar concentrations of sAPPα and APP 17mer peptide (derived from sAPPα) augmented eNOS expression. Further analysis established that γ-aminobutyric acid type B receptor subunit 1 and Krüppel-like factor 2 may function as downstream molecular targets significantly contributing to BACE2/APP/sAPPα-induced up-regulation of eNOS. In agreement with studies on cultured human endothelium, endothelium-dependent relaxations to acetylcholine and basal production of cyclic GMP were impaired in cerebral arteries of BACE2-deficient mice. We propose that in the brain blood vessels, BACE2 may function as a vascular protective protein.

Citing Articles

Secretase promotes AD progression: simultaneously cleave Notch and APP.

Yang K, Zhang J, Feng M, Yao K, Liu Y, Zhou M Front Aging Neurosci. 2024; 16:1445470.

PMID: 39634655 PMC: 11615878. DOI: 10.3389/fnagi.2024.1445470.

Cerebrovascular Endothelial Dysfunction: Role of BACE1.

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PMID: 38868939 PMC: 11269044. DOI: 10.1161/ATVBAHA.124.320798.

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