Title : Inhibiting beta-Amyloid-Associated Alzheimer's Pathogenesis In Vitro and In Vivo by a Multifunctional Dimeric Bis(12)-hupyridone Derived from Its Natural Analogue - Hu_2015_J.Mol.Neurosci_55_1014 |
Author(s) : Hu S , Wang R , Cui W , Zhang Z , Mak SH , Xu D , Choi C , Tsim KWK , Carlier PR , Lee M , Han Y |
Ref : Journal of Molecular Neuroscience , 55 :1014 , 2015 |
Abstract :
Fibrillar aggregates of beta-amyloid protein (Abeta) is the main constituent of senile plaques and considered to be one of the causative events in the pathogenesis of Alzheimer's disease (AD). Compounds that could inhibit the formation of Abeta fibrils and block Abeta fibrils-associated toxicity may have therapeutic potential to combat AD. Bis(12)-hupyridone (B12H) is a multifunctional homodimer derived from huperzine A, which is an anti-AD drug in China. In the current study, the inhibitory effect of B12H on the formation of Abeta fibrils and their associated toxicity was investigated both in vitro and in vivo. By using Thioflavin T fluorescence assay, we found that B12H (0.3-3 muM) directly inhibited Abeta fibrils formation following co-incubation of B12H and Abeta1-40 at 37 degrees C for 6 days in vitro. However, huperzine A, at the same concentrations, did not show significant inhibitory effect on Abeta1-40 fibrils formation. Moreover, B12H markedly reduced Abeta1-40-induced cytotoxicity in cultured SH-SY5Y cells, as evidenced by the increase in cell viability, the decrease in lactate dehydrogenase release, and the reduction of apoptotic nuclei. Most importantly, B12H (0.2 and 0.4 mg/kg) reduced intracerebroventricular Abeta1-40 infusion-induced cognitive and memory impairments in rats, as evidenced by the decrease in escape latency and the increase in the spatial bias in Morris water maze test along with increasing choline acetyltransferase activity and decreasing acetylcholinesterase activity. Collectively, our study provided novel sights into the potential application of B12H in AD treatment. |
PubMedSearch : Hu_2015_J.Mol.Neurosci_55_1014 |
PubMedID: 25407821 |
Hu S, Wang R, Cui W, Zhang Z, Mak SH, Xu D, Choi C, Tsim KWK, Carlier PR, Lee M, Han Y (2015)
Inhibiting beta-Amyloid-Associated Alzheimer's Pathogenesis In Vitro and In Vivo by a Multifunctional Dimeric Bis(12)-hupyridone Derived from Its Natural Analogue
Journal of Molecular Neuroscience
55 :1014
Hu S, Wang R, Cui W, Zhang Z, Mak SH, Xu D, Choi C, Tsim KWK, Carlier PR, Lee M, Han Y (2015)
Journal of Molecular Neuroscience
55 :1014