Effects of Magnesium Orotate, Benfotiamine and a Combination of Vitamins on Mitochondrial and Cholinergic Function in the TgF344-AD Rat Model of Alzheimer’s Disease

Abstract

Glucose hypometabolism, mitochondrial dysfunction, and cholinergic deficits have been reported in early stages of Alzheimer’s disease (AD). Here, we examine these parameters in TgF344-AD rats, an Alzheimer model that carries amyloid precursor protein and presenilin-1 mutations, and of wild type F344 rats. In mitochondria isolated from rat hippocampi, we found reductions of complex I and oxidative phosphorylation in transgenic rats. Further impairments, also of complex II, were observed in aged (wild-type and transgenic) rats. Treatment with a “cocktail” containing magnesium orotate, benfotiamine, folic acid, cyanocobalamin, and cholecalciferol did not affect mitochondrial activities in wild-type rats but restored diminished activities in transgenic rats to wild-type levels. Glucose, lactate, and pyruvate levels were unchanged by age, genetic background, or treatment. Using microdialysis, we also investigated extracellular concentrations of acetylcholine that were strongly reduced in transgenic animals. Again, ACh levels in wild-type rats did not change upon treatment with nutrients, whereas the cocktail increased hippocampal acetylcholine levels under physiological stimulation. We conclude that TgF344-AD rats display a distinct mitochondrial and cholinergic dysfunction not unlike the findings in patients suffering from AD. This dysfunction can be partially corrected by the application of the “cocktail” which is particularly active in aged rats. We suggest that the TgF344-AD rat is a promising model to further investigate mitochondrial and cholinergic dysfunction and potential treatment approaches for AD.

Sexual dimorphism in the peripheral metabolic homeostasis and behavior in the TgF344‐AD rat model of Alzheimer's disease

“…Furthermore, ex vivo assessment of hippocampal mitochondria activity has shown that both 6‐to‐7‐month‐old and 15‐to‐16‐month‐old Tg rats display reduced capacity for oxidative phosphorylation and decreased complex I activity compared to WT controls. The older group in this study also displayed reduced complex II activity relative to age‐matched WT controls (Viel et al, 2021 ), further demonstrating the presence of mitochondrial dysfunction in this model of AD. Taken together with our data, these demonstrate that altered metabolism, both central and peripheral, is a noteworthy feature in this model of AD.…”

Non‐transgenic guinea pig strains exhibit divergent age‐related changes in hippocampal mitochondrial respiration

“…Transgenic rodent model of AD had lower maximal complex I and complex II respiration compared to wild type control and these differences were exacerbated with age. 43 In our study, Hartley guinea pigs did not have any age-related differences in maximal stimulated complex I (Figure 2C) or complex I and II (Figure 3D,E) respiration, contrary to our hypotheses. However, because this was the first investigation of age-related changes in guinea pig hippocampal mitochondrial function, we also made comparisons with the non-transgenic PET guinea pig that has less severe age-related changes in the brain.…”

Effects of Combining Biofactors on Bioenergetic Parameters, Aβ Levels and Survival in Alzheimer Model Organisms

“…In our case, which is not a deficit model, we did not observe any improvement in ATP level, MPP, O 2 consumption or citrate synthase activity in SH-SY5Y-APP 695 cells ( Figure 4 ). In a study by Viel et al using a similar cocktail consisting of some of our compounds, the mitochondrial complex activity in a transgenic rat model was increased to that of wild type rats [ 28 ]. This effect is not found in our case, possibly due to the additional substances contained in the cocktail, which had been the decisive factor here.…”

“…A cocktail containing some of our tested compounds had a positive effect on AD symptoms in a TgF344-AD rat model. This could raise the mitochondrial function of the transgenic rats to the level of the wild-type rats [ 28 ]. Here, folic acid, magnesium-orotate and vitamin B6 in different combinations were tested in cellular and an invertebrate model of AD.…”