miRNA 933 Expression by Endothelial Cells is Increased by 27-Hydroxycholesterol and is More Prevalent in Plasma from Dementia Patients

Abstract

Alzheimer’s disease (AD) etiology is complex; gene and environmental risk factors may interact to predispose to disease. From single nucleotide polymorphism analyses and genome-wide association studies, a number of candidate risk genes for the onset of AD have been identified and cluster around lipid metabolism and inflammation. We hypothesized that endothelial cells which line the blood-brain barrier are likely to be critical mediators of systemic metabolism within the brain. Therefore, we have studied the effect of 27 hydroxycholesterol (27-OHC) on microvascular endothelial cell (HMVEC) redox state, inflammatory cytokine secretion, and microRNA (miR) expression. Using a transwell method, we have studied directional secretion profiles for the proinflammatory cytokines TNFα and IL-6 and confirmed that 27-OHC induces discrete and directional inflammatory molecular signatures from HMVEC. The lipids caused depletion of cellular glutathione and cytokine secretion is HMVEC-redox state-dependent. Discovery miR expression change in HMVEC with and without 27-OHC treatment was undertaken. We selected three genes for further analysis by qPCR; miR-144 and 146 expression, which are anti-inflammatory and redox regulating modulators, were not affected significantly by 27-OHC. However, increased expression of a putative neurotrophic regulatory factor miR933 in HMVEC with 27-OHC was confirmed by qPCR. In plasma from patients with dementia, all three miR were found at significantly elevated levels compared to healthy older adults. These data highlight that 27-OHC has an important regulatory effect on endothelial microvascular cells to increase expression of a miR (–933) and secretion of inflammatory cytokines that are elevated in plasma from dementia patients.

NF‐κB‐mediated inflammatory damage is differentially affected in SH‐SY5Y and C6 cells treated with 27‐hydroxycholesterol

“…Increasing numbers of studies have suggested that 27‐hydroxycholesterol (27‐OHC), an oxidative metabolite of cholesterol, may cause inflammation in the brain and is associated with an increased risk of dementia including AD (Dias, Brown, Shabir, Polidori, & Griffiths, ; Testa et al, ,). Our recent studies showed the toxic effect of 27‐OHC in C6 glioma cells and in the brains of Sprague–Dawley rats fed a high‐cholesterol diet.…”

EXPRESSION OF SELECTED miRNAs IN CIRCULATING BLOOD OF EARLY AND LATE-ONSET ALZHEIMER DISEASE PATIENTS

“…AD-related alterations in the expression of miRNAs have been described by several studies and these alterations have been reported not only in disease-related brain regions but also in peripheral body fluids such as CSF (14)(15)(16)(17), blood (18), plasma (19) and serum (20). Compared to brain tissue, peripheral samples, including blood, plasma, and serum are much easier to collect and determination of miRNA expression profiles in peripheral components enables these miRNAs to be used as a source of non-invasive biomarkers in AD diagnosis.…”

Association between MicroRNA-4669 Polymorphism and Ischemic Stroke in a Korean Population

“…Thus, authors suggested circulating miRNA-933 as a feasible predictor for ASCVD at the early stage [31]. On the contrary, other study reported that 27-hydroxycholesterol, a cholesterol metabolite, increased the level of miRNA-933 in microvascular endothelial cells along with the elevation of TNF- α and IL-6 [32]. Given these reports together with our result, miRNA-933 may play a role in the development and/or severity of vascular diseases although the mechanism has not been established.…”