Curr Alzheimer Res. 2015;12(5):424-33.

Inhibition of β-amyloid Aggregation By Albiflorin, Aloeemodin And Neohesperidin And Their Neuroprotective Effect On Primary Hippocampal Cells Against β-amyloid Induced Toxicity.

Ho SL, Poon CY, Lin C, Yan T, Kwong DW, Yung KK, Wong MS, Bian Z, Li HW.

Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China. hwli@hkbu.edu.hk.

 

Abstract

Being one of the hallmarks of Alzheimer’s disease, β-amyloid (Aβ) aggregates induce complicated neurotoxicity. Evidences show that the underlying mechanism of neurotoxicity involves a glutamate receptor subtype, N-methyl-D-aspartate (NMDA) receptor, an increase in intracellular calcium(II) ion loading as well as an elevation in oxidation stress. In this work, among the 35 chemical components of Chinese herbal medicines (CHMs) being screened for inhibitors of Aβ aggregation, four of them, namely albiflorin, aloeemodin, neohesperidin and physcion, were found for the first time to exhibit a potent inhibitory effect on Aβ(1-40) and Aβ(1-42) aggregation. Their neuroprotective capability on primary hippocampal neuronal cells was also investigated by MTT assay, ROS assay and intracellular calcium(II) ion concentration measurement. It was interesting to find that physcion was rather toxic to neuronal cells while albiflorin, aloeemodin and neohesperidin reduced the toxicity and ROS induced by both monomeric and oligomeric Aβ species. In addition, albiflorin was particularly powerful in maintaining the intracellular Ca(2+) concentration.

PMID: 25938872

 

SUPPLEMENTS:

Background:

Traditional Chinese medicine (TCM) has been practiced in China for millennia; many studies have applied Chinese herbal medicine (CHM) for clinical treatment of diseases and CHMs are of high potential to be a good source for treatment of Alzheimer’s disease (AD). Herein, we investigated the therapeutic effect of 35 compounds extracted from CHMs and their potential clinical applications in treating Alzheimer’s disease (AD). As β-amyloid (Aβ) peptides especially Aβ1-40 and Aβ1-42 are the major protein components found in the Aβ plaques, we first studied the inhibitory effect of CHM compounds on the aggregation of Aβ1-40 and Aβ1-42. Amongst the 35 CHM compounds, we discovered that Albiflorin, Aloeemodin, Neohesperidin, and Physcion exhibited an excellent inhibitory effect on preventing both Aβ1-40 and Aβ1-42 from aggregation, while Albiflorin, Aloeemodin, and Neohesperidin also produced a neuroprotective effect on primary hippocampal cells against the neurotoxicity induced by Aβ species.

Method:

The inhibitory study of the CHMs against the aggregation of Aβ1-40 was done by monitoring the seed-mediated growth of Aβ fibrils, where the resultant fibrils were labeled with Thioflavin T and visualized under the total internal reflection fluorescence microscopy (TIRFM) imaging system. By co-incubating the CHMs with the Aβ1-40 monomer in 1:1 ratio, we found that four of the CHMs, namely Albiflorin, Aloeemodin, Neohesperidin, and Physcion, inhibited the fibrillation process of Aβ1-40. The four CHMs were then applied to study the inhibitory effect on the more toxic Aβ aggregates, Aβ1-42. The results from the ThT assays have proven that the four CHMs inhibit the aggregation of Aβ1-42, the result was further confirmed by TEM. The underlying inhibitory mechanism was investigated by measuring the circular dichroism spectra of the Aβ1-42 monomer upon mixing with the four CHMs. Alternations of the peak position and amplitude in the spectra were observed upon the addition of the CHMs, which indicated that the β-sheet conformation was diminished and a new structural conformation was established.

The cytotoxicity of the four CHMs was determined by MTT assay. The data showed that the four CHMs are generally of low toxicity in the micro-molar range on human SH-SY5Y cells. As albiflorin, aloeemodin and neophesperidin are non-toxic to the neuronal cells, the clinical application of these three CHMs was further investigated using primary hippocampal cell. The MTT results showed that albiflorin, aloeemodin and neophesperidin provided a protection for the primary neuronal cell against the monomeric Aβ-induced toxicity. Among the three CHM compounds, aloeemodin is the most potent compound that protects the neuronal cell against the neurotoxicity induced by oligomeric Aβ1-40 and Aβ1-42. The neuroprotective mechanism of the compounds was further investigated by reactive oxygen species (ROS) and calcium (II) ion imaging measurements. All three CHM compounds were found to be able to attenuate the toxic ROS generation induced by the Aβ species. Meanwhile, albiflorin was found to be capable of maintaining the intercellular Ca2+ ion level upon the Aβ1-42 attack.

 

LHW fig1

Figure 1. The ROS level of primary hippocampal cells as induced by the oligomer Aβ1-40 and Aβ1-42 was attenuated by the addition of the three CHM compounds.

 

Importance of the study:

Herein, we have investigated the potential clinical applications of 35 compounds extracted from Chinese herbal medicine. Amongst the 35 compounds, three of them namely, albiflorin, aloeemodin and neophesperidin were found to be able to i) inhibit the formation of Aβ aggregates, ii) protect the neuronal cell against the ROS induced toxicity, and iii) reduce Ca2+ ion reflux induced by the toxic Aβ species. The three CHM compounds are of high potential to prevent and treat AD.

 

References:

See-Lok Ho, Chung-Yan Poon, Chengyuan Lin, Ting Yan, Daniel Wai-Jing Kwong, Ken Kin-Lam Yung, Man-Shing Wong, Zhaoxiang Bian and Hung-Wing Li, Current Alzheimer’s Research (2015), 12(5), 424-433.

 

Acknowledgements: We are thankful to the financial support of research grants, Interdisciplinary Research Matching Scheme of Hong Kong Baptist University (RC-IRMS/12-13/01), Health and Medical Research Fund (HMRF 01122066) from the Hong Kong Government. We also thank the Shenzhen Municipal Science and Technology Industry and Information Technology Commission Research (JCYJ20120817163755064).

 

Contact: Hung-Wing Li, Ph.D., Associate Professor Department of Chemistry Hong Kong Baptist University Hong Kong

hwli@hkbu.edu.hk http://chem.hkbu.edu.hk/hwli

 

 

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