Upregulation of Vitamin C Transporter Functional Expression in 5xFAD Mouse Intestine

Abstract

The process of obtaining ascorbic acid (AA) via intestinal absorption and blood circulation is carrier-mediated utilizing the AA transporters SVCT1 and SVCT2, which are expressed in the intestine and brain (SVCT2 in abundance). AA concentration is decreased in Alzheimer’s disease (AD), but information regarding the status of intestinal AA uptake in the AD is still lacking. We aimed here to understand how AA homeostasis is modulated in a transgenic mouse model (5xFAD) of AD. AA levels in serum from 5xFAD mice were markedly lower than controls. Expression of oxidative stress response genes (glutathione peroxidase 1 (GPX1) and superoxide dismutase 1 (SOD1)) were significantly increased in AD mice jejunum, and this increase was mitigated by AA supplementation. Uptake of AA in the jejunum was upregulated. This increased AA transport was caused by a marked increase in SVCT1 and SVCT2 protein, mRNA, and heterogeneous nuclear RNA (hnRNA) expression. A significant increase in the expression of HNF1α and specific protein 1 (Sp1), which drive SLC23A1 and SLC23A2 promoter activity, respectively, was observed. Expression of hSVCT interacting proteins GRHPR and CLSTN3 were also increased. SVCT2 protein and mRNA expression in the hippocampus of 5xFAD mice was not altered. Together, these investigations reveal adaptive up-regulation of intestinal AA uptake in the 5xFAD mouse model.

The level of active DNA demethylation compounds in leukocytes and urine samples as potential epigenetic biomarkers in breast cancer patients

“…This hypothesis may be supported by our observations that vitamin C level in leukocytes of breast cancer patients was similar to the level of this compound in leukocytes of healthy subjects. As a matter of fact, studies on mice incapable of synthesizing vitamin C in vivo revealed the increase in SVCT mRNA expression level in liver 74 , 75 , cerebellum 75 or intestine 76 . Moreover, in vitro study demonstrated that breast cancer cell lines transport vitamin C via SVCT2 transporter 77 .…”

Shared peripheral blood biomarkers for Alzheimer’s disease, major depressive disorder, and type 2 diabetes and cognitive risk factor analysis

“…Previous studies have shown that HNF1A mutations are associated with fatty acid and glucose metabolism [ 61 ] and lead to the adult onset of young type 3 diabetes [ 62 ] and coronary artery disease [ 63 ]. In addition, a team has verified HNF1A in AD by designing animal experiments [ 64 ]. The HNF1A gene encodes the hepatocyte nuclear factor 1-alpha, the protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes.…”

“…The HNF1A gene encodes the hepatocyte nuclear factor 1-alpha, the protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. A team designed experiments to observe a significant increase in the expression of hepatocyte nuclear factor 1-alpha driving SLC23A1 and SLC23A2 promoter activity, respectively [ 64 ]. As for MDD and T2DM, most of the existing studies remain at the genetic level, and there are still few studies on proteins.…”

Impact of IL-21-associated peripheral and brain crosstalk on the Alzheimer’s disease neuropathology

“…These transgenic mice represent an accelerated AD model, developing AD pathologies by 2 months of age and reductions in synaptophysin, neuron loss and memory impairments that become evident by 5–6 months of age. We have used this AD model in our previous publications [ 3 , 5 , 40 ]. Early (1–3 months) male and female 5xFAD mice and their littermate controls were used for the experiments.…”