High-dose of vitamin C supplementation reduces amyloid plaque burden and ameliorates pathological changes in the brain of 5XFAD mice

S-Y Kook,S Kang,Y Kim,R Park,S H Baik,I Mook-Jung,H Lee,K-M Lee,M-Y Cha

doi:10.1038/cddis.2014.26

Abstract

Blood–brain barrier (BBB) breakdown and mitochondrial dysfunction have been implicated in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disease characterized by cognitive deficits and neuronal loss. Besides vitamin C being as one of the important antioxidants, recently, it has also been reported as a modulator of BBB integrity and mitochondria morphology. Plasma levels of vitamin C are decreased in AD patients, which can affect disease progression. However, investigation using animal models on the role of vitamin C in the AD pathogenesis has been hampered because rodents produce with no dependence on external supply. Therefore, to identify the pathogenic importance of vitamin C in an AD mouse model, we cross-bred 5 familial Alzheimer's disease mutation (5XFAD) mice (AD mouse model) with ι-gulono-γ-lactone oxidase (Gulo) knockout (KO) mice, which are unable to synthesize their own vitamin C, and produced Gulo KO mice with 5XFAD mice background (KO-Tg). These mice were maintained on either low (0.66 g/l) or high (3.3 g/l) supplementation of vitamin C. We found that the higher supplementation of vitamin C had reduced amyloid plaque burden in the cortex and hippocampus in KO-Tg mice, resulting in amelioration of BBB disruption and mitochondrial alteration. These results suggest that intake of a larger amount of vitamin C could be protective against AD-like pathologies.

Highlights

It remains unclear whether vitamin C directly influences brain pathology in Alzheimer’s disease (AD) patients and/or in animal models, as mouse is able to synthesize vitamin C endogenously
Amyloid plaque burden is decreased in the cortex and hippocampus of the high-dose supplemented group of 5XFAD mice
As vitamin C acts as a vital antioxidant molecule in the brain and neurodegenerative diseases typically involve high levels of oxidative stress, a number of reports have suggested that vitamin C has potential therapeutic roles against AD, ischemic stroke, Parkinson’s disease and Huntington’s disease.[32,33,34,35]

Summary

Introduction

It remains unclear whether vitamin C directly influences brain pathology in AD patients and/or in animal models, as mouse is able to synthesize vitamin C endogenously. To examine the precise effect of vitamin C on AD pathology in vivo, we successfully generated a transgenic mice (knockout (KO)-Tg mice) by crossing 5 familial Alzheimer’s disease mutation (5XFAD) mice, AD model mice, with mice lacking i-gulono-g-lactone oxidase (Gulo), the enzyme required for the biosynthesis of ascorbic acid.[9] These mice have heavy depositions of amyloid plaques in the brain and are unable to synthesize vitamin C in vivo. In KO-Tg mice, the mice were maintained on a low level of vitamin C supplementation (0.66 g/l, 2-fold above the minimum anti-scurvy level) or a high level (3.3 g/l, 10-fold level above the minimum requirement) to determine the direct effect of vitamin C on AD pathology. We have found that sufficient vitamin C supplementation significantly reduces amyloid deposition in both the cortex and

Methods

Results

Conclusion