Inhibiting β-Amyloid-Associated Alzheimer’s Pathogenesis In Vitro and In Vivo by a Multifunctional Dimeric Bis(12)-hupyridone Derived from Its Natural Analogue

Shengquan Hu, Rui Wang, Wei Cui, Zaijun Zhang, Shinghung Mak, Daping Xu, Chunglit Choi, Karl Wahkeung Tsim, Paul R. Carlier, Mingyuen Lee, Yifan Han

Research output: Journal article publicationJournal articleAcademic researchpeer-review

15 Citations (Scopus)

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 Aβ1–40at 37 °C for 6 days in vitro. However, huperzine A, at the same concentrations, did not show significant inhibitory effect on Aβ1–40fibrils 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 Aβ1–40infusion-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.
Original languageEnglish
Pages (from-to)1014-1021
Number of pages8
JournalJournal of Molecular Neuroscience
Volume55
Issue number4
DOIs
Publication statusPublished - 10 Mar 2015

Keywords

  • Alzheimer’s disease
  • Aβ fibrils
  • Bis(12)-hupyridone
  • Cell viability
  • Memory impairment
  • Thioflavin T

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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