Vitamin C Deficiency in the Brain Impairs Cognition, Increases Amyloid Accumulation and Deposition, and Oxidative Stress in APP/PSEN1 and Normally Aging Mice

Abstract

Subclinical vitamin C deficiency is widespread in many populations, but its role in both Alzheimer’s disease and normal aging is understudied. In the present study we decreased brain vitamin C in the APPSWE/PSEN1deltaE9 mouse model of Alzheimer’s disease, by crossing APP/PSEN1+ bigenic mice with SVCT2+/− heterozygous knockout mice, which have lower numbers of the sodium-dependent vitamin C transporter required for neuronal vitamin C transport. SVCT2+/− mice performed less well on the rotarod task at both 5 and 12 months of age compared to littermates. SVCT2+/− and APP/PSEN1+, mice, and the combination genotype SVCT2+/−APP/PSEN1+, were also impaired on multiple tests of cognitive ability (olfactory memory task, Y-maze alternation, conditioned fear, Morris water maze). In younger mice, both low vitamin C (SVCT2+/−) and APP/PSEN1 mutations increased brain cortex oxidative stress (malondialdehyde, protein carbonyls, F2-isoprostanes) and decreased total glutathione compared to wild-type controls. SVCT2+/− mice also had increased amounts of both soluble and insoluble Aβ1-42 and a higher Aβ1-42/1-40 ratio. By 14 months of age, oxidative stress levels were similar among groups, but there were more amyloid-β plaque deposits in both hippocampus and cortex of SVCT2+/−APP/PSEN1+ mice compared to APP/PSEN1+ mice with normal brain vitamin C. The data suggest that even moderate intracellular vitamin C deficiency plays an important role in accelerating amyloid pathogenesis, particularly during early stages of disease development, and that these effects are likely modulated by oxidative stress pathways.

Mitochondrial dysfunction in the APP/PSEN1 mouse model of Alzheimer’s disease and a novel protective role for ascorbate

“…APP/PSEN1 mice develop appreciable amyloid beta (Aβ) accumulation and oxidative stress from 5–6 months of age [38]. Additionally, APP/PSEN1 mice exhibit structural abnormalities in mitochondria at 6 months [44–46].…”

“…Animal and cell culture studies offer additional evidence that supplementation with ASC not only ameliorates oxidative stress, but also mitigates the production of Aβ [33–37]. Previously published data from our group show a significant increase in soluble Aβ 1–42 and Aβ 1–40 peptides in cortical tissue from SVCT2 +/− ; APP/PSEN1 mice at 6 months compared with APP/PSEN1 mice that have normal SVCT2 transporter expression, indicating that compromised ASC capacity increases the momentum of Alzheimer’s disease pathological processes [38]. Consistent with this data, other groups showed chronic ascorbate (ASC) supplementation resulted in a decrease in total soluble Aβ 1–42 and a reduction in overall amyloid plaque burden in Alzheimer’s disease mouse models [33,34].…”

“…This could potentially introduce an easy and inexpensive lifestyle modification to slow the progression of sporadic Alzheimer’s disease. We measured mitochondrial respiration, membrane potential, ROS generation and energy production in cortical mitochondrial isolates from the APP/PSEN1 mouse model for Alzheimer’s disease at 4 months of age, before the emergence of cognitive deficits and significant amyloid deposition [38,43]. We also investigated the extent to which ASC affects these functions in mice with heterozygous expression of the highly selective SVCT2 transporter (SVCT2 +/− ).…”

Vitamin C Transporter (SVCT2) Distribution in Developing and Adult Brains

“…In these experiments, the researchers did not consider that the observations could be attributed to a failure in vitamin C recycling. Although vitamin C deficiency in the brain has been associated with increased oxidative stress, which could be stimulating ideal conditions to trigger certain pathologies, including Alzheimer's disease [54], DHA has recently been proposed as a molecule that would trigger neuronal death [39]. As shown in Figure 1, we propose that CNS pathologies could be associated with reduced astrocytic vitamin C recycling, resulting in the accumulation of DHA in neurons, which would trigger cell death.…”

Nutritional strategies in the management of Alzheimer\'s disease: systematic review and meta-analysis

“…Studies performed in humans and animals exhibit a correlation between vitamin C deficiency and oxidative stress markers, noticeably increased in AD (73). A study in AD models observed that a moderate vitamin C deficiency, mostly during initial stages of disease development, has a significant effect in accelerating amyloid pathogenesis, which may be modulated by oxidative stress pathways (74). In another study performed with normal rats supplemented in a long-term with two different dosages of ascorbic acid, it was found that in the lowest dose supplementation the anxiolytic effects of ascorbic acid were more typical, while memory improvement seemed to be confined to the highest dose (75).…”