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.
Highlights
The rising prevalence of Alzheimer’s disease (AD) is a substantial burden to individuals and to health care systems, making the development of new therapeutic concepts for treating AD an important goal [1,2]
While magnesium orotate and benfotiamine did not significantly affect respiration, the administration of the cocktail caused an increase of complex I respiration in transgenic rats (Figure 2A)
The treatment with cocktail was very effective in transgenic rats: it increased respiration by 60% so that complex I respiration in transgenic rats reached the activity of wild-type animals (Figure 2B)
Summary
The rising prevalence of Alzheimer’s disease (AD) is a substantial burden to individuals and to health care systems, making the development of new therapeutic concepts for treating AD an important goal [1,2]. Available drugs, such as acetylcholinesterase (AChE) inhibitors and memantine, merely act symptomatically and only delay the progression of the disease. Recent suggestions for AD drug developments focused on other aspects of the disease, especially energy metabolism and mitochondrial function [4]. Several papers described reductions of mitochondrial complex activities in AD patients [7,8].
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