Abstract
The toxic aggregates of amyloid beta (Aβ) disrupt the cell membrane, induce oxidative stress and mitochondrial dysfunction, and eventually lead to Alzheimer’s disease (AD). Intervening with this cytotoxic aggregation process has been suggested as a potential therapeutic approach for AD and other protein misfolding diseases. Traditional Chinese Medicine (TCM) has been used to treat AD and related cognitive impairment for centuries with obvious efficacy. Extracts or active ingredients of TCMs have been reported to inhibit the aggregation and cytotoxicity of Aβ. However, there is a lack of systematic research on the anti-Aβ aggregation effects of TCM components. In this study, we performed a systematic screening to identify the active ingredients of TCM against the cytotoxic aggregation of Aβ42. Through a literature and database survey, we selected 19 TCM herbals frequently used in the treatment of AD, from which 76 major active chemicals without known anti-amyloid effects were further screened. This took place through two rounds of MTT-based screening detection of the cytotoxicity of these chemicals and their effects on Aβ42-induced cytotoxicity, respectively. Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) and sinapic acid (SA) were found to be less toxic, and they inhibited the cytotoxicity of Aβ42. Further studies demonstrated that TSG and SA concentration-dependently attenuated the amyloidosis and membrane disruption ability of Aβ42. Thus, we identified two novel chemicals (TSG and SA) against the cytotoxic aggregation of Aβ42. Nonetheless, further exploration of their therapeutic potential is warranted.
Highlights
Alzheimer’s disease (AD) is a common age-associated neurodegenerative disease, characterized by progressive memory and neuronal loss combined with cognitive impairment (Hung and Fu, 2017)
We further identified the 10 most frequently used AD-treating Traditional Chinese Medicine (TCM) summarized in these 20 articles (Supplementary Table S1), and a total of 24 TCMs were found, of which 19 appeared at least twice (Supplementary Table S2)
TCMs have been clinically used in the prevention and treatment of AD and related cognitive impairment with obvious efficacy (Li et al, 2006; Li et al, 2015; Ong et al, 2018)
Summary
Alzheimer’s disease (AD) is a common age-associated neurodegenerative disease, characterized by progressive memory and neuronal loss combined with cognitive impairment (Hung and Fu, 2017). Extracts or active ingredients of TCMs show anti-AD effects via multiple mechanisms, such as improving acetylcholine levels and decreasing acetyl cholinesterase activity (Wang et al, 2018), suppressing abnormal phosphorylation of Tau protein (Ma et al, 2019), inhibiting neuronal apoptosis (Wang et al, 2019; Zhang et al, 2019), anti-oxidation (Tong et al, 2018), anti-inflammation (Maione et al, 2018), and inhibiting Aβ42 deposition (Shi et al, 2018; Zhang et al, 2019). We performed a systematic investigation to identify the active ingredients of TCM against the cytotoxic aggregation of Aβ42. We selected the 19 most commonly used TCMs in treating AD and related cognitive impairments through literature investigation (Yan, 2007; Yan and Chen, 2008; Hu et al, 2012; Howes et al, 2017; Lin et al, 2019), from which 76 chemicals were selected through composition investigation. Transmission electron microscopy (TEM), dynamic light scattering (DLS) analysis and dye leakage assays were further performed to investigate the effects of these chemicals on the aggregation and membrane disruption ability of Aβ42
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