Cell Death Dis. 2014 Feb 27;5:e1083. doi: 10.1038/cddis.2014.26.
High-dose of vitamin C supplementation reduces amyloid plaque burden and ameliorates pathological changes in the brain of 5XFAD mice.
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 Chad 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.
Amyloid plaque burden is decreased in the cortex and hippocampus of the high-supplementation group of 5XFAD mice. (a) Coronal serial sections of brains from 6-month-old mice (n=4 for each of the groups) were stained with anti-Aβ antibody (green; 4G8) and imaged by confocal microscopy. There were no signals in the frontal cortex of KO-WT mice in either of the two treatment. 4G8-positive areas were decreased in the frontal cortex of KO-Tg on the high-dose vitamin C treatment. Scale bar=600 μm. The section shown is at the interaural level, 4.78 mm; Bregma, −0.98 mm (Fig. 23 in Franklin and Paxinos57). (b) Frontal cortex of KO-Tg mice of both treatment groups was magnified. (a and d) Somatosensory region; (b and c) motor region. Scale bar=100 μm. (c) Coronal serial sections of brains from 6-month-old mice (n=4 for each of the groups) were stained with anti-Aβ antibody (green; 4G8) and imaged by confocal microscopy. There were no signals in the hippocampus of KO-WT mice in either treatment groups. Plaques were particularly decreased in the hippocampus of KO-Tg on the high-dose vitamin C treatment. Scale bar=600 μm. The section shown is at the interaural level, 1.86 mm; Bregma, −1.94 mm (Fig. 47 in Franklin and Paxinos57). (d) Hippocampus of KO-Tg mice of both treatment groups was magnified. Nuclei were stained with 4′-6-diamidino-2-phenylindole. Scale bar=100 μm. (e) Compared with the low-dose supplemented KO-Tg mice, the high-dose supplementation KO-Tg mice exhibited significantly less plaque burden in the cortex and hippocampus. Both P values (***P<0.001 and *P<0.05) mean the high-dose versus the low-dose supplemented KO-Tg group