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Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice.
- Source :
-
Brain : a journal of neurology [Brain] 2010 May; Vol. 133 (Pt 5), pp. 1342-51. Date of Electronic Publication: 2010 Apr 12. - Publication Year :
- 2010
-
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.
- Subjects :
- Alzheimer Disease genetics
Alzheimer Disease pathology
Amyloid beta-Peptides antagonists & inhibitors
Amyloid beta-Peptides genetics
Animals
Brain metabolism
Cerebral Cortex metabolism
Cognition Disorders etiology
Dose-Response Relationship, Drug
Drug Administration Schedule
Fursultiamin pharmacology
Glycogen Synthase Kinases antagonists & inhibitors
Glycogen Synthase Kinases metabolism
Isoenzymes antagonists & inhibitors
Isoenzymes metabolism
Maze Learning
Memory drug effects
Mice
Mice, Transgenic
Phosphorylation drug effects
Plaque, Amyloid drug effects
Plaque, Amyloid pathology
Presenilin-1 genetics
Swimming
Thiamine administration & dosage
Thiamine metabolism
tau Proteins metabolism
Alzheimer Disease metabolism
Alzheimer Disease psychology
Amyloid beta-Peptides metabolism
Cognition drug effects
Cognition Disorders metabolism
Cognition Disorders psychology
Presenilin-1 metabolism
Thiamine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2156
- Volume :
- 133
- Issue :
- Pt 5
- Database :
- MEDLINE
- Journal :
- Brain : a journal of neurology
- Publication Type :
- Academic Journal
- Accession number :
- 20385653
- Full Text :
- https://doi.org/10.1093/brain/awq069