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

Trevor Teafatiller,Munjal M Acharya,Veedamali S Subramanian,Anshu Agrawal,Christopher W Heskett,Janet E Baulch,Jonathan S Marchant

doi:10.3390/nu13020617

Trevor Teafatiller, Munjal M Acharya + Show 5 more

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https://doi.org/10.3390/nu13020617

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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.

Highlights

Published: 14 February 2021Vitamin C is important for maintaining normal cellular function and overall health as it acts as an essential cofactor for several key enzymatic reactions [1,2].Maintaining vitamin C body homeostasis seems to protect against age-related cognitive decline and Alzheimer’s disease (AD) [3]
These findings suggest enhanced oxidative stress in the jejunum of AD mice that is correctable by vitamin C supplementation
0.01 for both) in the jejunum of mice compared to icantly increased (p < 0.01 for both) in the jejunum of 5xFAD mice compared to WT littermates (Figure 5A,B). These findings suggest that glyoxylate reductase/hydroxypyruvate reductase (GRHPR) and Calsyntenin 3 (CLSTN3) may mates (Figure 5A,B). These findings suggest that GRHPR and CLSTN3 may a contribute to the upregulation of ascorbic acid (AA) uptake in the jejunum of 5xFAD mice

Summary

Introduction

Vitamin C (ascorbic acid; AA) is important for maintaining normal cellular function and overall health as it acts as an essential cofactor for several key enzymatic reactions [1,2]. Maintaining vitamin C body homeostasis seems to protect against age-related cognitive decline and Alzheimer’s disease (AD) [3]. Deficiency of vitamin C is implicated in cognitive dysfunction and accelerates β-amyloid accumulation and deposition in AD [4,5,6,7]. C can play a role in immunosenescence and inflammation, the trademarks of biological aging [6]. Plasma vitamin C levels in AD patients are significantly lower than that of normal individuals, which may correlate with adverse health outcomes [6,8,9,10].

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