title: Inhibiting β-amyloid-associated Alzheimer's pathogenesis in vitro and in vivo by a multifunctional dimeric bis(12)-hupyridone derived from its natural analogue.
abstract: Fibrillar aggregates of β-amyloid protein (Aβ) 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 Aβ fibrils and block Aβ 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 Aβ 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 μM) directly inhibited Aβ fibrils formation following co-incubation of B12H and Aβ1-40 at 37 °C for 6 days in vitro. However, huperzine A, at the same concentrations, did not show significant inhibitory effect on Aβ1-40 fibrils formation. Moreover, B12H markedly reduced Aβ1-40-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 Aβ1-40 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.
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.
authors.forename: Shengquan
authors.initials: S
authors.lastname: Hu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Shinghung
authors.initials: S
authors.lastname: Mak
authors.forename: Daping
authors.initials: D
authors.lastname: Xu
authors.forename: Chunglit
authors.initials: C
authors.lastname: Choi
authors.forename: Karl Wahkeung
authors.initials: KW
authors.lastname: Tsim
authors.forename: Paul R
authors.initials: PR
authors.lastname: Carlier
authors.forename: Mingyuen
authors.initials: M
authors.lastname: Lee
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D018782:Maze Learning; D008568:Memory; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy*; D015363:Quinolones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018696:Neuroprotective Agents; D015363:Quinolones; C528260:bis(12)-hupyridone