Our previous studies proposed that Alzheimer’s disease(AD) is a metabolic disorder and hypothesized that abnormal brain glucose metabolism inducing multiple pathophysiological cascades contributes to AD pathogenesis. Aging is one of the great significant risk factors for AD. Membrane aging is first prone to affect the function and structure of the brain by impairing glucose metabolism.We presume that risk factors of AD, including genetic factors(e.g., the apolipoprotein E ε4 allele and genetic mutations) and non-genetic factors(such as fat, diabetes,and cardiac failure) accelerate biomembrane aging and lead to the onset and development of the disease. In this review,we further modify our previous hypothesis to demonstrate‘‘membrane aging’’ as an initial pathogenic factor that results in functional and structural alterations of membranes and, consequently, glucose hypometabolism and multiple pathophysiological cascades.
Abstract To date, we still lack disease-modifying thera- pies for Alzheimer＇s disease （AD）. Here, we report that long-term administration of benfotiamine improved the cognitive ability of patients with AD. Five patients with mild to moderate AD received oral benfotiamine （300 mg daily） over 18 months. All patients were examined by positron emission tomography with Pittsburgh compound B （PiB-PET） and exhibited positive imaging with β- amyloid deposition, and three received PiB-PET imaging at follow-up. The five patients exhibited cognitive improve- ment as assayed by the Mini-Mental Status Examination （MMSE） with an average increase of 3.2 points at month 18 of benfotiamine administration. The three patients who received follow-up PiB-PET had a 36.7% increase in the average standardized uptake value ratio in the brain com- pared with that in the first scan. Importantly, the MMSE scores of these three had an average increase of 3 points during the same period. Benfotiamine significantly improved the cognitive abilities of mild to moderate AD patients independently of brain amyloid accumulation. Ourstudy provides new insight to the development of disease- modifying therapy.
Objective To determine whether high glucose enhances β-amyloid （Aβ） production in HEK293 Swedish mutant （APPsw） cells with Aβ precursor protein （APP） overexpression, and whether under this condition benfotiamine reduces the increased Aβ production. Methods HEK293 APPsw cells were cultured with different concentrations of glucose for different times. TheAβ content in the supernatant was determined by ELISA. To investigate the mechanism by which benfotiamine reduced Aβ production, glycogen synthase kinase-3 （GSK-3） activity and expression were measured after the cells were cultured with 5.5 g/L glucose for 12 h. Results With 1.0, 3.0, 4.5, 5.5, 6.5, 7.5, 8.5, or 10.5 g/L glucose, Aβ production by HEK293 APPsw cells was highest in the presence of 5.5 g/L glucose for 6 and 12 h. The difference in Aβ content between 5.5 and 1.0 g/L was most marked after incubation for 12 h. Benfotiamine at 20 and 40 μg/mL significantly reduced Aβ production in cells incubated with 5.5 g/L glucose for 12 h. Moreover, 40 μg/mL benfotiamine significantly enhanced the ratio of phosphorylated GSK-3 to total GSK-3, together with consistent down-regulation of GSK-3 activity. Conclusion High glucose increases Aβ production by HEK293 APPsw cells while benfotiamine prevents this increase. This is correlated with the modulation of GSK-3 activity.
