A Systematic Screening of Traditional Chinese Medicine Identifies Two Novel Inhibitors Against the Cytotoxic Aggregation of Amyloid Beta

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.

Congo Red‐Derived Carbon Dots: Simultaneously as Fluorescence Probe for Protein Aggregates, Inhibitor for Protein Aggregation, and Scavenger of Free Radicals

“…The concentrations of the above obtained protein aggregates samples were both calculated based on the concentration of respective incubated protein monomer. [ 8 . 51 ]…”

“…[51] As for Aβ 42 aggregates preparation, Aβ 42 powder was first dissolved in 60 mm NaOH aqueous solution to a stock concentration of 200 µm, which was then diluted with phosphate buffered saline (PBS, containing 100 mm NaCl, pH 7.4) to 20 µm for incubation at 37 °C for 6 h to acquire the Aβ 42 aggregates stock sample, and finally stored at −20 °C for further use. [8] Besides, referring to previous works, [27,52] α-synuclein and lysozyme aggregates were prepared. The concentrations of the above obtained protein aggregates samples were both calculated based on the concentration of respective incubated protein monomer.…”

“…[3,4] Specifically, for the AD-associated proteins, Aβ 42 is a more prevalent amyloidogenic protein in the senile plaques, exhibiting faster aggregation rate in vitro and higher neurotoxicity in vivo than Aβ 40 , [4][5][6][7] which is a widely-accepted model aggregative protein in the AD study. [8] The formed protein aggregates, especially the soluble oligomers and protofibrils, could pose high cytotoxicity, causing the damage of cell membrane, dysfunction of organelles (such as mitochondrion and golgi apparatus) as well as cellular oxidative stress with elevated free radical level. [9][10][11][12] Therefore, detection of protein aggregates, inhibition of protein aggregation, and scavenging of free radical would be of great significance for the diagnosis and treatment of the protein aggregation diseases.…”

The emerging role of autophagy and mitophagy in tauopathies: From pathogenesis to translational implications in Alzheimer’s disease

“…It is estimated that approximately 57.4 million individuals were living with AD globally in 2019 ( GBD 2019 Dementia Forecasting Collaborators, 2022 ). The main pathological features of AD include brain atrophy, neuronal loss, intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, and accumulation of amyloid-beta (Aβ) in cerebral vessels and brain parenchyma ( DeTure and Dickson, 2019 ; Tiwari et al, 2019 ; Ma et al, 2021 ). Discussions of the underlying molecular mechanisms of AD are ongoing.…”

Hydroxycinnamic Acid Derivatives from Coffee Extracts Prevent Amyloid Transformation of Alpha-Synuclein

“…It should be especially noted that among the studied cinnamic acid derivatives exhibiting an anti-amyloid effect there were natural compounds, namely ferulic acid [ 15 ], caffeic acid [ 17 ], rosmarinic acid [ 15 , 18 ], chlorogenic acid [ 19 , 20 ], sinapinic acid [ 21 ], and 3,4-dimethoxycinnamic acids [ 9 , 11 ]. Champagne wine extracts rich in these components have been shown to protect neurons against 5-S-cysteinyl-dopamine in vitro [ 22 ].…”