Docosahexaenoic acid, one of the main structural fatty acids in brain lipids, inhibits on the fibrillation of amyloid β peptide in vivo and in vitro

2009 ◽  
Vol 65 ◽  
pp. S116
Author(s):  
Michio Hashimoto ◽  
Shahdat Hossain ◽  
Masanori Katakura ◽  
Shido Osamu
Keyword(s):  
Fatty Acids ◽  
Docosahexaenoic Acid ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Brain Lipids

Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

2018 ◽  
Vol 15 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Dominik Szwajgier ◽  
Ewa Baranowska-Wojcik ◽  
Kamila Borowiec
Keyword(s):  
Phenolic Acids ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Amyloid Β Peptide ◽  
Beneficial Effects ◽  
Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

scholarly journals Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia

2021 ◽  
Vol 118 (15) ◽  
pp. e2025847118
Author(s):  
Dorit Trudler ◽  
Kristopher L. Nazor ◽  
Yvonne S. Eisele ◽  
Titas Grabauskas ◽  
Nima Dolatabadi ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Amyloid Β ◽  
Induced Pluripotent Stem Cell ◽  
Amyloid Β Peptide ◽  
Human Microglia ◽  
Pyrin Domain ◽  
Toll Like Receptor 2 ◽  
Induced Pluripotent

Parkinson’s disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn–antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.

scholarly journals Neuropharmacological Effects of Quercetin: A Literature-Based Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Md. Shahazul Islam ◽  
Cristina Quispe ◽  
Rajib Hossain ◽  
Muhammad Torequl Islam ◽  
Ahmed Al-Harrasi ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neuroprotective Effect ◽  
Animal Experiments ◽  
Amyloid Β ◽  
Neuronal Injury ◽  
Amyloid Β Peptide ◽  
Protective Effects ◽  
Neuroprotective Effects

Quercetin (QUR) is a natural bioactive flavonoid that has been lately very studied for its beneficial properties in many pathologies. Its neuroprotective effects have been demonstrated in many in vitro studies, as well as in vivo animal experiments and human trials. QUR protects the organism against neurotoxic chemicals and also can prevent the evolution and development of neuronal injury and neurodegeneration. The present work aimed to summarize the literature about the neuroprotective effect of QUR using known database sources. Besides, this review focuses on the assessment of the potential utilization of QUR as a complementary or alternative medicine for preventing and treating neurodegenerative diseases. An up-to-date search was conducted in PubMed, Science Direct and Google Scholar for published work dealing with the neuroprotective effects of QUR against neurotoxic chemicals or in neuronal injury, and in the treatment of neurodegenerative diseases. Findings suggest that QUR possess neuropharmacological protective effects in neurodegenerative brain disorders such as Alzheimer’s disease, Amyloid β peptide, Parkinson’s disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. In summary, this review emphasizes the neuroprotective effects of QUR and its advantages in being used in complementary medicine for the prevention and treatment o of different neurodegenerative diseases.

An Aβ42 variant that inhibits intra- and extracellular amyloid aggregation and enhances cell viability

2018 ◽  
Vol 475 (19) ◽  
pp. 3087-3103 ◽  
Author(s):  
Ofek Oren ◽  
Victor Banerjee ◽  
Ran Taube ◽  
Niv Papo
Keyword(s):  
Amyloid Fibrils ◽  
Neuronal Cells ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Amyloid Β Peptide ◽  
Cell Cytotoxicity ◽  
Amyloid Aggregation ◽  
Molar Ratios

Aggregation and accumulation of the 42-residue amyloid β peptide (Aβ42) in the extracellular matrix and within neuronal cells is considered a major cause of neuronal cell cytotoxicity and death in Alzheimer's disease (AD) patients. Therefore, molecules that bind to Aβ42 and prevent its aggregation are therapeutically promising as AD treatment. Here, we show that a non-self-aggregating Aβ42 variant carrying two surface mutations, F19S and L34P (Aβ42DM), inhibits wild-type Aβ42 aggregation and significantly reduces Aβ42-mediated cell cytotoxicity. In addition, Aβ42DM inhibits the uptake and internalization of extracellularly added pre-formed Aβ42 aggregates into cells. This was the case in both neuronal and non-neuronal cells co-expressing Aβ42 and Aβ42DM or following pre-treatment of cells with extracellular soluble forms of the two peptides, even at high Aβ42 to Aβ42DM molar ratios. In cells, Aβ42DM associates with Aβ42, while in vitro, the two soluble recombinant peptides exhibit nano-molar binding affinity. Importantly, Aβ42DM potently suppresses Aβ42 amyloid aggregation in vitro, as demonstrated by thioflavin T fluorescence and transmission electron microscopy for detecting amyloid fibrils. Overall, we present a new approach for inhibiting Aβ42 fibril formation both within and outside cells. Accordingly, Aβ42DM should be evaluated in vivo for potential use as a therapeutic lead for treating AD.

scholarly journals Curcumin in Health and Diseases: Alzheimer’s Disease and Curcumin Analogues, Derivatives, and Hybrids

2020 ◽  
Vol 21 (6) ◽  
pp. 1975 ◽  
Author(s):  
Eirini Chainoglou ◽  
Dimitra Hadjipavlou-Litina
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Specific Activity ◽  
Curcuma Longa ◽  
Amyloid Β ◽  
Hydroxyl Group ◽  
Amyloid Β Peptide ◽  
Curcumin Analogues

Worldwide, Alzheimer’s disease (AD) is the most common neurodegenerative multifactorial disease influencing the elderly population. Nowadays, several medications, among them curcumin, are used in the treatment of AD. Curcumin, which is the principal component of Curcuma longa, has shown favorable effects forsignificantly preventing or treating AD. During the last decade, the scientific community has focused their research on the optimization of therapeutic properties and on the improvement of pharmacokinetic properties of curcumin. This review summarizes bibliographical data from 2009 to 2019 on curcumin analogues, derivatives, and hybrids, as well as their therapeutic, preventic, and diagnostic applications in AD. Recent advances in the field have revealed that the phenolic hydroxyl group could contribute to the anti-amyloidogenic activity. Phenyl methoxy groups seem to contribute to the suppression of amyloid-β peptide (Aβ42) and to the suppression of amyloid precursor protein (APP) andhydrophobic interactions have also revealed a growing role. Furthermore, flexible moieties, at the linker, are crucial for the inhibition of Aβ aggregation. The inhibitory activity of derivatives is increased with the expansion of the aromatic rings. The promising role of curcumin-based compounds in diagnostic imaging is highlighted. The keto-enol tautomerism seems to be a novel modification for the design of amyloid-binding agents. Molecular docking results, (Q)SAR, as well as in vitro and in vivo tests highlight the structures and chemical moieties that are correlated with specific activity. As a result, the knowledge gained from the existing research should lead to the design and synthesis ofinnovative and multitargetedcurcumin analogues, derivatives, or curcumin hybrids, which would be very useful drug and tools in medicine for both diagnosis and treatment of AD.

scholarly journals Bacterial production and direct functional screening of expanded molecular libraries for discovering inhibitors of protein aggregation

2019 ◽  
Vol 5 (10) ◽  
pp. eaax5108 ◽  
Author(s):  
Dafni C. Delivoria ◽  
Sean Chia ◽  
Johnny Habchi ◽  
Michele Perni ◽  
Ilias Matis ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Early Stage ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Functional Screening ◽  
Parkinson’S Diseases ◽  
Aggregation Inhibitors ◽  
Molecular Libraries

Protein misfolding and aggregation are associated with a many human disorders, including Alzheimer’s and Parkinson’s diseases. Toward increasing the effectiveness of early-stage drug discovery for these conditions, we report a bacterial platform that enables the biosynthesis of molecular libraries with expanded diversities and their direct functional screening for discovering protein aggregation inhibitors. We illustrate this approach by performing, what is to our knowledge, the largest functional screen of small-size molecular entities described to date. We generated a combinatorial library of ~200 million drug-like, cyclic peptides and rapidly screened it for aggregation inhibitors against the amyloid-β peptide (Aβ42), linked to Alzheimer’s disease. Through this procedure, we identified more than 400 macrocyclic compounds that efficiently reduce Aβ42 aggregation and toxicity in vitro and in vivo. Finally, we applied a combination of deep sequencing and mutagenesis analyses to demonstrate how this system can rapidly determine structure-activity relationships and define consensus motifs required for bioactivity.

scholarly journals EphA4 regulates Aβ production via BACE1 expression in neurons

2020 ◽  
Author(s):  
Kensuke Tamura ◽  
Yung-Wen Chiu ◽  
Azusa Shiohara ◽  
Yukiko Hori ◽  
Taisuke Tomita
Keyword(s):  
Genome Wide Association Study ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Mrna Levels ◽  
Bace1 Expression ◽  
A Genome ◽  
Ephrin Ligands ◽  
Aβ Production

Abstract BackgroundSeveral lines of evidence suggest that the aggregation and deposition of amyloid-β peptide (Aβ) initiate the pathology of Alzheimer disease (AD). Recently, a genome- wide association study demonstrated that a single-nucleotide polymorphism proximal to the EPHA4 gene, which encodes a receptor tyrosine kinase, is associated with AD risk. However, the molecular mechanism of EphA4 in the pathogenesis of AD, particularly in Aβ production, remains unknown.MethodsTo clarify the molecular regulatory mechanism of EphA4 in detail, we performed several pharmacological and biological experiments both in vitro and in vivo. In addition, we referred to two public RNAseq datasets to confirm the changes in EPHA4 mRNA expression levels in the brains of AD patients.ResultsWe demonstrated that EphA4 is responsible for the regulation of Aβ production. Pharmacological inhibition of EphA4 signaling and knockdown of Epha4 led to increased Aβ levels accompanied by increased expression of β-site APP cleaving enzyme 1 (BACE1), which is an enzyme responsible for Aβ production. On the other hand, EPHA4 overexpression and activation of EphA4 signaling via ephrin ligands decreased Aβ levels. In particular, the sterile-alpha motif domain of EphA4 was necessary for the regulation of Aβ production. Finally, EPHA4 mRNA levels were significantly reduced in the brains of AD patients, and negatively correlated with BACE1 mRNA levels.ConclusionsOur results indicate a novel mechanism of Aβ regulation by EphA4, which is involved in AD pathogenesis.

Polyphenols from Traditional Chinese Medicine and Mediterranean Diet are effective against Aβ toxicity in vitro and in vivo in Caenorhabditis elegans

2022 ◽  
Author(s):  
Adriana Gea-González ◽  
Samanta Hernandez-Garcia ◽  
Paula Henarejos-Escudero ◽  
Pedro Martinez-Rodriguez ◽  
Francisco Garcia-Carmona ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Mediterranean Diet ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Naturally Occurring ◽  
Toxicity In Vitro

The potential of naturally-occurring polyphenols as nutraceuticals to prevent and/or treat Alzheimer’s disease is studied. Five structurally related flavones and four tyrosols were tested in vitro in human amyloid-β peptide...

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