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

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.

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

“…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]. …”

The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease

“…As microgliosis and astrocytosis are prominent aspects of this Alzheimer disease mouse model indicative of neuro inflammation, [35][36][37][38] we identified the effect of ASS234 on neuroinflammation through the evaluation of the immuno histochemical distribution of the astrocyte marker protein GFAP (Fig. 5A, B and E) and of the microglia/macrophage specific protein Iba1 (Fig.…”

Caveolin-1–mediated internalization of the vitamin C transporter SVCT2 in microglia triggers an inflammatory phenotype

“…For example, heterozygosity for a null allele of Slc23a2 (Slc23a2 +/− ) reduces the abundance of ascorbate in the CNS and increases the deposition of b-amyloid plaques in a mouse model of Alzheimer's disease (APP/PSEN1) (20). Ascorbate treatment not only reverses some of the cognitive deficits in APP/PSEN1 or in APP/PSEN1/Gulo −/− Alzheimer's disease models (21,22) but also reduces amyloid plaque burden in the brains of 5XFAD/Gulo −/− mice (23). In addition, abnormal ascorbate transport (24,25) is linked to the motor dysfunction observed in the R6/2 transgenic mouse model of Huntington's disease (24).…”