Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice.
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.
Pan
Xiaoli
X
Department of Neurology, Zhongshan Hospital & Shanghai Medical College, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
Gong
Neng
N
Zhao
Jing
J
Yu
Zhe
Z
Gu
Fenghua
F
Chen
Jia
J
Sun
Xiaojing
X
Zhao
Lei
L
Yu
Meijing
M
Xu
Zhiru
Z
Dong
Wenxin
W
Qin
Yan
Y
Fei
Guoqiang
G
Zhong
Chunjiu
C
Xu
Tian-Le
TL
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism* / Q000523:psychology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005666:Fursultiamin / Q000494:pharmacology; D038341:Glycogen Synthase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D018782:Maze Learning; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D058225:Plaque, Amyloid / Q000187:drug effects / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D013550:Swimming; D013831:Thiamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D007527:Isoenzymes; D053764:Presenilin-1; D016875:tau Proteins; D005666:Fursultiamin; D038341:Glycogen Synthase Kinases; D013831:Thiamine; C013835:benphothiamine