Powerful beneficial effects of benfotiamine on cognitive impairment and  -amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice

Abstract

Reduction of glucose metabolism in brain is one of the main features of Alzheimer's disease. Thiamine (vitamin B1)-dependent processes are critical in glucose metabolism and have been found to be impaired in brains from patients with Alzheimer's disease. However, thiamine treatment exerts little beneficial effect in these patients. Here, we tested the effect of benfotiamine, a thiamine derivative with better bioavailability than thiamine, on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 transgenic mouse. We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. Unexpectedly, these effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine were effective in increasing the levels of free thiamine in the brain. Most notably, benfotiamine, but not fursultiamine, significantly elevated the phosphorylation level of glycogen synthase kinase-3alpha and -3beta, and reduced their enzymatic activities in the amyloid precursor protein/presenilin-1 transgenic brain. Therefore, in the animal Alzheimer's disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely to include the suppression of glycogen synthase kinase-3 activities. These results suggest that, unlike many other thiamine-related drugs, benfotiamine may be beneficial for clinical Alzheimer's disease treatment.

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease

“…Here, we present the results of a clinical case study showing the potential of benfotiamine as a disease-modifying drug for AD. As a derivative of thiamine with better bioavailability, benfotiamine has been demonstrated to exert beneficial effects against abnormal glucose metabolism and its consequences via multiple mechanisms, including the elimination of oxidative stress [16,17] and the inhibition of glycogen synthase kinase-3 [18], which are both considered to be major pathogenic factors that cause neurodegeneration in AD. The better bioavailability and the pharmacological effects via multiple mechanisms against abnormal glucose metabolism and its consequences may explain why benfotiamine administration but not thiamine supplementation [24] had a long-term beneficial effect on cognitive ability in AD patients.…”

“…Our previous study demonstrated that benfotiamine improves cognitive impairment in a mouse model of AD (amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice) [18]. Here, we investigated the effects of benfotiamine on the cognitive ability and amyloid accumulation in the brain assayed by positron emission tomography with Pittsburgh compound-B (PiB-PET) in five patients with mild to moderate AD.…”

“…TDP, thiamine monophosphate (TMP), and thiamine levels were determined using high performance liquid chromatography (HPLC), as previously described [18]. Briefly, 150 lL of whole blood anticoagulated with heparin was collected and immediately deproteinized with an equal volume of 7.4% perchloric acid.…”

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

“…All female APP/PS1 transgenic mice (4.5 months old) with a confirmed genotype were produced by the Model Animal Research Center of Nanjing University (Pan et al ., 2010). Female transgenic mice were used because female mice manifest an early deficit in spatial memory in the MWM test and develop greater Aβ burden compared to age‐matched male mice (Gallagher et al ., 2013).…”

Correlat ion of thiamine metabolite levels with cognitive function in the non-demented elderly

“…The levels of thiamine, TMP, and TDP were measured using HPLC as previously described in detail [18] . Briefl y, 150 μL of 7.4% perchloric acid was immediately added to 150 Apolipoprotein E Genotype Analysis APOE alleles were detected using the ABI real-time Taqman SNP genotyping assay (L ife Technologies, Carlsbad, CA) according to the manufacturer's instructions.…”