Natural flavonoid hesperetin blocks amyloid ß-protein fibrillogenesis, depolymerizes preformed fibrils and alleviates cytotoxicity caused by amyloids.

The aggregation of ß-amyloid (Aß) peptides to form amyloid plaques is one of the primary hallmarks for Alzheimer's disease (AD). Dietary flavonoid supplements containing hesperetin have an ability to decline the risk of developing AD, but the molecular mechanism is still unclear. In this work, hesperetin, a flavanone abundant in citrus fruits, has been proven to prevent the formation of Aß aggregates and depolymerized preformed fibrils in a concentration-dependent fashion. Hesperetin inhibited the conformational conversion from the natural structure to a ß-sheet-rich conformation. It was found that hesperetin significantly reduced the cytotoxicity and relieved oxidative stress eventuated by Aß aggregates in a concentration-dependent manner. Additionally, the beneficial effects of hesperetin were confirmed in Caenorhabditis elegans, including the inhibition of the formation and deposition of Aß aggregates and extension of their lifespan. Finally, the results of molecular dynamics simulations showed that hesperetin directly interacted with an Aß42 pentamer mainly through strong non-polar and electrostatic interactions, which destroyed the structural stability of the preformed pentamer. To summarize, hesperetin exhibits great potential as a prospective dietary supplement for preventing and improving AD.

Bifunctional Inhibitor Lentinan Inhibits Fibrillogenesis of Amyloid-ß Protein and α-Synuclein and Alleviates Their Cytotoxicity: In Vitro and In Vivo Studies.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases in the world. Misfolding of ß-amyloid (Aß) and α-synuclein (α-syn) and subsequent fibril formation are closely associated with the pathogenesis of AD and PD, respectively. Lentinan is a natural product commonly used in medicine and dietary supplements. It has potential antitumor, anti-inflammatory, and antiviral effects, but the underlying mechanism of its action on AD and PD remains unclear. In this study, lentinan inhibited the formation of Aß and α-syn fibers in a dose-dependent manner and disrupted their mature fibers. Lentinan inhibited the conversion of Aß and α-syn conformations to ß-sheet-rich conformations. Additionally, lentinan protected Caenorhabditis elegans against damage caused by the accumulation of Aß and α-syn aggregation and prolonged their lifespan. Notably, the beneficial effects of lentinan in AD and PD mice were also demonstrated, including ameliorating the cognitive and memory impairments in AD mice and behavioral deficits in PD mice. Finally, molecular interactions between lentinan and Aß/α-syn pentamers were also explored using molecular docking.

Dietary soybeans worsen dextran sodium sulfate-induced colitis by disrupting intestinal ecology.

Food mediates susceptibility to inflammatory bowel diseases (IBDs) associated with the microbiome. Existing studies suggest that a high-sugar and high-fat diet promotes IBDs, but whether a plant-based diet is fully harmless to IBD improvement remains unknown. In this study, for the first time, we assessed the effect of soybean and its carbohydrates on dextran sodium sulfate (DSS)-induced colitis. In a DSS-induced colitis mouse model (BALB/C WT), the oral administration of soybeans worsened colitis, which was associated with higher disease activity index, histology score and expression of pro-inflammatory cytokines, and lower expression of anti-inflammatory cytokines. Here, 16S rRNA sequencing and elimination of gut bacteria by antibiotics showed that the exacerbating colitis caused by soybeans depends on the changes in the intestinal flora. Furthermore, the gavage of soybean carbohydrates such as sucrose and raffinose-family oligosaccharides altered the intestinal microbiota and worsened inflammation. When co-cultured with macrophages (RAW 264.7), the metabolites of the disordered intestinal flora, isolated Escherichia coli and purified LPS showed high macrophage toxicity to inhibit pathogen clearance. These results indicate that the intake of soybeans and soybean carbohydrates is not conducive to recovery from IBDs based on changes in gut microbiota and metabolites affecting the activities of macrophages.

Modulation of the Gut Microbiota and Glycometabolism by a Probiotic to Alleviate Amyloid Accumulation and Cognitive Impairments in AD Rats.

SCOPE: Regulating the gut microecology by probiotics is an efficient strategy to rational prevention and treatment of Alzheimer's disease (AD). However, there is currently a lack of well-known probiotic species in the protection against AD, and the involved mechanism has not been clearly interpreted. METHODS AND RESULTS: Herein, Lactobacillus plantarum MA2 (MA2), a functional probiotic isolated from traditional Chinese Tibetan kefir grains, is demonstrated to improve the cognitive deficits and anxiety-like behaviors in the d-galactose/AlCl3 induced AD rats, and attenuate the neuronal degeneration and Aß accumulation in the brain. Moreover, the study finds MA2 could alleviate the intestinal mucosal impairments, and impedes the activation of microglia and neuroinflammation through TLR4/MYD88/NLRP3 signaling pathway. 16S rRNA sequencing and metabolomic analysis indicate that MA2 reshapes the gut microbiota structure and composition, and remarkably modulates the glycometabolism. In that case, the exopolysaccharides (EPS) that derived from MA2 is furtherly proved with inhibitory effects on the Aß42 aggregation and amyloid-induced cytotoxicity. CONCLUSION: MA2 or MA2 EPS may be used as functional food and nutritional supplement for regulating the gut microbiota and metabolism disorders in AD. This study is of great significance to develop new intervention and therapeutic strategy on AD using probiotics and their metabolites.

Design of carboxylated single-walled carbon nanotubes as highly efficient inhibitors against Aß40 fibrillation based on the HyBER mechanism.

Misfolding and the subsequent self-assembly of amyloid-ß protein (Aß) is very important in the occurrence of Alzheimer's disease (AD). Thus, inhibition of Aß aggregation is currently an effective method to alleviate and treat AD. Herein, a carboxylated single-walled carbon nanotube (SWCNT-COOH) was rationally designed based on the hydrophobic binding-electrostatic repulsion (HyBER) mechanism. The inhibitory effect of SWCNT-COOH on Aß fibrillogenesis was first studied. Based on the results of thioflavin T fluorescence and atomic force microscopy imaging assays, it was shown that SWCNT-COOH can not only effectively inhibit Aß aggregation, but also depolymerize the mature fibrils of Aß. In addition, its inhibitory action will be affected by the content of carboxyl groups. Moreover, the influence of SWCNT-COOH on cytotoxicity induced by Aß was investigated by the MTT method. It was found that SWCNT-COOH can produce an anti-Aß neuroprotective effect in vitro. Molecular dynamics simulations showed that SWCNT-COOH significantly destroyed the overall and internal structural stability of an Aß40 trimer. Moreover, SWCNT-COOH interacted strongly with the N-terminal region, turn region and C-terminal region of the Aß40 trimer via hydrogen bonds, salt bridges and π-π interactions, which triggered a large structural disturbance of the Aß40 trimer, reduced the ß-sheet content of the Aß40 trimer and led to more disorder in these regions. All the above data not only reveal the suppressive effect of SWCNT-COOH on Aß aggregation, but also reveal its inhibitory mechanism, which provides a useful clue to exploit anti-Aß drugs in the future.

Fast green FCF inhibits Aß fibrillogenesis, disintegrates mature fibrils, reduces the cytotoxicity, and attenuates Aß-induced cognitive impairment in mice.

Fast green FCF (FGF) is often used in foods, pharmaceuticals, and cosmetics. However, little is known about the interactions of FGF with amyloid-ß protein (Aß) associated with Alzheimer's disease. In this study, the inhibitory effects of FGF on Aß fibrillogenesis, the disruption of preformed Aß fibrils, the reduction of Aß-induced cytotoxicity, and the attenuation of Aß-induced learning and memory impairments in mice were investigated. FGF significantly inhibited Aß fibrillogenesis and disintegrated the mature fibrils as evidenced by thioflavin T fluorescence and atomic force microscopy studies. Co-incubation of Aß with FGF greatly reduced Aß-induced cytotoxicity in vitro. Moreover, FGF showed a protective effect against cognitive impairment in Aß-treated mice. Molecular dynamics simulations further showed that FGF could synergistically interact with the Aß17-42 pentamer via electrostatic interactions, hydrogen bonds and π-π interactions, which reduced the ß-sheet content, and disordered random coils and bend structures of the Aß17-42 pentamer. This study offers a comprehensive understanding of the inhibitory effects of FGF against Aß neurotoxicity, which is critical for the search of effective food additives that can combat amyloid-associated disease.

Dual Effect of the Acidic Polysaccharose Ulvan on the Inhibition of Amyloid-ß Protein Fibrillation and Disintegration of Mature Fibrils.

The abnormal folding and aggregation of amyloid-ß protein (Aß) is the main reason for the occurrence and development of Alzheimer's disease (AD). The discovery of novel inhibitors against Aß aggregation is still the current research focus. Herein, we report the inhibitory effect of ulvan, an acidic polysaccharide from green algae of the genus Ulva, against Aß fibrillation using thioflavin T (ThT) fluorescence and atomic force microscopy (AFM) assays. It is shown that ulvan effectively inhibits Aß fibrillogenesis in a concentration-dependent manner and actively inhibits the formation of A11-reactive Aß oligomers, the most toxic Aß species. The circular dichroism spectrum reveals that ulvan blocks the conformational transition of Aß40 from the initial random coil to a ß-sheet structure, but it only delays the conformational transition of Aß42. It is also found that ulvan greatly reduces Aß-induced cytotoxicity by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, ulvan effectively downregulates intracellular reactive oxygen species production and protects PC12 cells from the damage caused by Aß fibrillation. Moreover, ulvan disaggregates preformed mature fibrils into off-pathway oligomers and greatly decreases their associated cytotoxicity, as revealed using ThT fluorescence, AFM, MTT, and dot-blotting assays. The above results not only fully describe the inhibitory effect of ulvan on Aß fibrillation and its related cytotoxicity but also provide novel ideas for the development of functional food ingredients from seaweed to treat AD.