Molecular mechanisms underlying reduced vitamin C transport process in Alzheimer's disease and its impact on neuroinflammation

University Of California-Irvine, Irvine CA

Investigators

Abstract

PROJECT SUMMARY Alzheimer’s disease (AD) is a major cause of age-related dementia. The underlying mechanisms are not well understood, but oxidative damage is a key component in AD pathogenesis. Vitamin C (vitC) is a powerful anti- oxidant that plays a major role in reducing oxidative stress and inflammation in the brain. AD subjects display a deficiency in vitC and several studies support the role of this vitamin in protection against the onset and progression of AD. Despite the beneficial effects of vitC on AD, what remains unknown are the underlying molecular mechanisms that lead to a deficiency of vitC in AD and how this deficiency enhances inflammation and pathogenesis of AD. VitC is an essential micronutrient that cannot be synthesized de novo or stored by the body and must be obtained from diet source. VitC uptake occurs through a Na+-dependent carrier-mediated process via sodium-dependent vitC transporters in the intestine (SVCT1 and SVCT2) and brain (SVCT2). Studies have shown that vitC supplementation failed to slow the cognitive decline observed in AD despite high dietary intake of vitC. The decreased absorption of vitC may be due to the reduced levels of expression of the vitC transporters in these important organs. Our preliminary findings indicate that expression of these transporters correlates inversely with advancing age in human and mouse brain and intestine. Further investigations revealed that inflammatory cytokines could reduce the expression of the vitC transporters in these organs. Neuro-inflammation, for example, has been implicated in AD pathology. When examining the effect of vitC on inflammation, our studies revealed that the increased NLRP3 inflammasome expression in AD may be regulated by vitC. Based on previous studies and our preliminary findings, we hypothesize that deficiency of vitC due to reduced functional expression of the vitC transporters in the brain and intestine enhances inflammation and promotes AD pathogenesis. The objective of this project is to investigate the molecular mechanisms underlying vitC deficiency and the associated inflammation. To test this hypothesis, we propose two specific aims: 1) to determine whether dysregulated intestinal vitC transport is responsible for decreased vitC levels in AD and 2) to determine the mechanisms by which vitC deficiency enhances the expression of NLRP3 and inflammation. We will use advanced in vivo mice models as well as state-of-the-art cell/molecular biological approaches in this application. The long term goal of this project is to develop novel therapeutics for reducing the severity of AD pathogenesis.