BACE2 deficiency impairs expression and function of endothelial nitric oxide synthase in brain endothelial cells

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.image

Cerebrovascular Endothelial Dysfunction: Role of BACE1

“…34 Of note, BACE2, close homologue of BACE1, is also expressed in the brain endothelial cells; however, BACE2 exerts endothelial protective effects thereby guarding cerebral vasculature from CAA. 63 We also would like to point out that findings obtained in old (18 months of age) eNOS-heterozygous (eNOS +/− ) knockout mice suggest that significantly higher levels of Aβ are produced and released from cerebral microvessels of eNOS +/− as compared with Aβ levels released from cerebral microvessels of agematched wild-type mice. 60 Notably, this increase of Aβ is detectable before any changes of Aβ levels in the brain parenchyma.…”

“…34 Of note, BACE2, close homologue of BACE1, is also expressed in the brain endothelial cells; however, BACE2 exerts endothelial protective effects thereby guarding cerebral vasculature from CAA. 63…”

BACE2 beyond β‐processing of APP, its neuroprotective role in cerebrovascular endothelium

“…In this issue of J Neurochem,Katusic et al show that in human brain microvascular endothelial cells (BMECs) the downregulation of BACE2 by small interfering RNA (BACE2siRNA) decreased the expression of eNOS and elevated levels of eNOS phosphorylated at the negative regulatory site Thr495 [p-eNOS(Thr495)], leading to reduced production of nitric oxide (NO)(He et al, 2023). In the brain, NO is an important signaling molecule that mediates neuronal survival, synaptic plasticity, vascular smooth muscle relaxation, and endothelial cell permeability (de laMonte et al, 2000).Vasculopathy in AD is characterized, in addition to Aβ deposition, by thickening and hyalinization of the media of small and medium-sized vessels, and increased apoptosis of vascular smooth muscle and endothelial cells, particularly involving white matter vessels, abnormalities that correlated with reduced eNOS expression levels in cerebral vessels (de laMonte et al, 2000).…”