myricetin and Alzheimer-Disease

Alzheimer's disease (AD) is the most common form of dementia characterized by presence of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Currently there are close to 50 million people living with dementia and this figure is expected to increase to 75 million by 2030 putting a huge burden on the economy due to the health care cost. Considering the effects on quality of life of patients and the increasing burden on the economy, there is an enormous need of new disease modifying therapies to tackle this disease. The current therapies are dominated by only symptomatic treatments including cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers but no disease modifying treatments exist so far. After several failed attempts to develop drugs against amyloidopathy, tau targeting approaches have been in the main focus of drug development against AD. After an overview of the tauopathy in AD, this review summarizes recent findings on the development of small molecules as therapeutics targeting tau modification, aggregation, and degradation, and tau-oriented multi-target directed ligands. Overall, this work aims to provide a comprehensive and critical overview of small molecules which are being explored as a lead candidate for discovering drugs against tauopathy in AD.

Topics: Alzheimer Disease; Animals; Benzodioxoles; Cholinesterase Inhibitors; Cholinesterases; Curcumin; Humans; Molecular Targeted Therapy; Neurofibrillary Tangles; Neuroprotective Agents; Phosphorylation; Plaque, Amyloid; Protein Aggregation, Pathological; Protein Processing, Post-Translational; Quinazolines; Receptors, N-Methyl-D-Aspartate; tau Proteins; Thiadiazoles

Pharmacological approaches directed toward Alzheimer disease are diversifying in parallel with a growing number of promising targets. Investigations on the microtubule-associated protein tau yielded innovative targets backed by recent findings about the central role of tau in numerous neurodegenerative diseases. In this review, we summarize the recent evolution in the development of nonpeptidic small molecules tau aggregation inhibitors (TAGIs) and their advancement toward clinical trials. The compounds are classified according to their chemical structures, providing correlative insights into their pharmacology. Overall, shared structure-activity traits are emerging, as well as specific binding modes related to their ability to engage in hydrogen bonding. Medicinal chemistry efforts on TAGIs together with encouraging in vivo data argue for successful translation to the clinic.

Topics: Alzheimer Disease; Animals; Clinical Trials as Topic; Humans; Hydrogen Bonding; Models, Molecular; Protein Binding; Protein Conformation; Structure-Activity Relationship; tau Proteins

Alzheimer's disease is a progressive brain disorder with characteristic symptoms and several pathological hallmarks. The concept of "one drug, one target" has not generated any new drugs since 2004. The new era of drug development in the field of AD builds upon rationally designed multi-target directed ligands that can better address the complexity of AD. Herewith, we designed ten novel derivatives of 2-propargylamino-naphthoquinone. The biological evaluation of these compounds includes inhibition of monoamine oxidase A/B, inhibition of amyloid-beta aggregation, radical-scavenging, and metal-chelating properties. Some of the compounds possess low cytotoxicity profile with an anti-inflammatory ability in the lipopolysaccharide-stimulated cellular model. All these features warrant their further testing in the field of AD.

Topics: Alzheimer Disease; Drug Design; Humans; Naphthoquinones; Structure-Activity Relationship

The search for novel and effective therapeutics for Alzheimer's disease (AD) is the main quest that remains to be resolved. The goal is to find a disease-modifying agent able to confront the multifactorial nature of the disease positively. Herewith, a family of huprineY-tryptophan heterodimers was prepared, resulting in inhibition of cholinesterase and neuronal nitric oxide synthase enzymes, with effect against amyloid-beta (Aβ) and potential ability to cross the blood-brain barrier. Their cholinesterase pattern of behavior was inspected using kinetic analysis in tandem with docking studies. These heterodimers exhibited a promising pharmacological profile with strong implication in AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Amyloid beta-Peptides; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Heterocyclic Compounds, 4 or More Rings; Humans; Molecular Structure; Neuroprotective Agents; Structure-Activity Relationship; Tryptophan

To develop drugs to treat Alzheimer's disease (AD) on the basis of the amyloid cascade hypothesis, the amyloid-β (Aβ) aggregation inhibitory activities of 110 extracts from mushrooms were evaluated by thioflavin T (Th-T) assays. The MeOH extract of

Topics: Agaricales; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Basidiomycota; Humans; Japan; Molecular Structure; Terpenes

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.

Topics: Alzheimer Disease; Aminoquinolines; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Brain; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Heterocyclic Compounds, 4 or More Rings; Humans; Molecular Dynamics Simulation; Molecular Structure; Neuroprotective Agents; Recombinant Proteins; Structure-Activity Relationship; tau Proteins

Alzheimer's disease is a serious neurologic disorder that cannot be cured completely. In this study, we targeted compounds that inhibit amyloid-beta (Aβ) aggregation, based on the amyloid cascade hypothesis. Ten compounds (1-10) were isolated from CHCl

Topics: Alzheimer Disease; Amyloid beta-Peptides; Basidiomycota; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Conformation; Resorcinols; Terpenes

Accumulation of tau protein aggregation plays a crucial role in neurodegenerative diseases, such as Alzheimer's disease (AD). Uncontrollable neuroinflammation and tau pathology form a vicious circle that further aggravates AD progression. Herein, we reported the synthesis of usnic acid derivatives and evaluation of their inhibitory activities against tau-aggregation and neuroinflammation. The inhibitory activity of the derivatives against the self-fibrillation of the hexapeptide AcPHF6 was initially screened by ThT fluorescence assay. Using circular dichroism and transmission electron microscopy, compound 30 showed the most potent inhibitory activity against AcPHF6 self-fibrillation. Compound 30 was further confirmed to inhibit the aggregation of full-length 2N4R tau protein by a heparin-induced mechanism. In addition, we investigated the anti-inflammatory activity of compound 30, and showed that compared with sodium usnate, it reduced NO release in LPS-stimulated mouse microglia BV2 cells. More importantly, 30 showed significant protective effects against okadaic acid-induced memory impairment in rats. Thus, 30 was a novel tau-aggregation and neuroinflammation inhibitor that represented a potential therapeutic candidate for AD.

Topics: Alzheimer Disease; Animals; Benzofurans; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Inflammation; Lipopolysaccharides; Male; Maze Learning; Mice; Models, Molecular; Molecular Structure; Nitric Oxide; Protein Aggregates; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; tau Proteins

Amyloid β (Aβ) aggregation plays an essential role in promoting the progression of Alzheimer's disease (AD). Therefore, the inhibition of Aβ aggregation is a potential therapeutic approach for AD. Herein, twenty-seven biflavonoids with different inter-flavonyl linkages and methoxy substitution patterns were isolated from several plants, and their Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biflavonoids; Humans

Alzheimer's disease (AD) is the main cause of dementia in people over 65 years. One of the major culprits in AD is the self-aggregation of amyloid-β peptide (Aβ), which has stimulated the search for small molecules able to inhibit Aβ aggregation. In this context, we recently reported a simple, but effective in vitro cell-based assay to evaluate the potential antiaggregation activity of putative Aβ aggregation inhibitors. In this work this assay was used together with docking and molecular dynamics simulations to analyze the anti-Aβ aggregation activity of several naturally occurring flavonoids and phenolic compounds. The results showed that rosmarinic acid, melatonin, and o-vanillin displayed zero or low inhibitory capacity, curcumin was found to have an intermediate inhibitory potency, and apigenin and quercetin showed potent antiaggregation activity. Finally, the suitability of the combined in vitro cell-based/in silico approach to distinguish between active and inactive compounds was further assessed for an additional set of flavonols and dihydroflavonols.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Apigenin; Benzaldehydes; Cinnamates; Depsides; Flavonoids; Humans; In Vitro Techniques; Molecular Structure; Peptide Fragments; Phenols; Quercetin; Rosmarinic Acid

The aggregation of the 42-residue amyloid β-protein (Aβ42) is involved in the pathogenesis of Alzheimer disease (AD). Numerous flavonoids exhibit inhibitory activity against Aβ42 aggregation, but their mechanism remains unclear in the molecular level. Here we propose the site-specific inhibitory mechanism of (+)-taxifolin, a catechol-type flavonoid, whose 3',4'-dihydroxyl groups of the B-ring plays a critical role. Addition of sodium periodate, an oxidant, strengthened suppression of Aβ42 aggregation by (+)-taxifolin, whereas no inhibition was observed under anaerobic conditions, suggesting the inhibition to be associated with the oxidation to form o-quinone. Because formation of the Aβ42-taxifolin adduct was suggested by mass spectrometry, Aβ42 mutants substituted at Arg(5), Lys(16), and/or Lys(28) with norleucine (Nle) were prepared to identify the residues involved in the conjugate formation. (+)-Taxifolin did not suppress the aggregation of Aβ42 mutants at Lys(16) and/or Lys(28) except for the mutant at Arg(5). In addition, the aggregation of Aβ42 was inhibited by other catechol-type flavonoids, whereas that of K16Nle-Aβ42 was not. In contrast, some non-catechol-type flavonoids suppressed the aggregation of K16Nle-Aβ42 as well as Aβ42. Furthermore, interaction of (+)-taxifolin with the β-sheet region in Aβ42 was not observed using solid-state NMR unlike curcumin of the non-catechol-type. These results demonstrate that catechol-type flavonoids could specifically suppress Aβ42 aggregation by targeting Lys residues. Although the anti-AD activity of flavonoids has been ascribed to their antioxidative activity, the mechanism that the o-quinone reacts with Lys residues of Aβ42 might be more intrinsic. The Lys residues could be targets for Alzheimer disease therapy.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Catechols; Humans; Lysine; Norleucine; Peptide Fragments; Quercetin

Reduced and carboxymethylated-kappa-casein (RCM-kappa-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Abeta), which is associated with Alzheimer's disease. In this study, a series of flavonoids, many known to be inhibitors of Abeta fibril formation, were screened for their ability to inhibit RCM-kappa-CN fibrilisation, and the results were compared with literature data on Abeta inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-kappa-CN fibril formation. IC(50) values were between 10- and 200-fold higher with RCM-kappa-CN than literature results for Abeta fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-kappa-CN assay make it an economic alternative first screen for Abeta inhibitory activity, especially for use with large compound libraries.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Caseins; Flavonoids; Humans; Methylation; Milk; Structure-Activity Relationship

Alzheimer disease is characterized by the abnormal aggregation of amyloid beta peptide into extracellular fibrillar deposits known as amyloid plaques. Soluble oligomers have been observed at early time points preceding fibril formation, and these oligomers have been implicated as the primary pathological species rather than the mature fibrils. A significant issue that remains to be resolved is whether amyloid oligomers are an obligate intermediate on the pathway to fibril formation or represent an alternate assembly pathway that may or may not lead to fiber formation. To determine whether amyloid beta oligomers are obligate intermediates in the fibrillization pathway, we characterized the mechanism of action of amyloid beta aggregation inhibitors in terms of oligomer and fibril formation. Based on their effects, the small molecules segregated into three distinct classes: compounds that inhibit oligomerization but not fibrillization, compounds that inhibit fibrillization but not oligomerization, and compounds that inhibit both. Several compounds selectively inhibited oligomerization at substoichiometric concentrations relative to amyloid beta monomer, with some active in the low nanomolar range. These results indicate that oligomers are not an obligate intermediate in the fibril formation pathway. In addition, these data suggest that small molecule inhibitors are useful for clarifying the mechanisms underlying protein aggregation and may represent potential therapeutic agents that target fundamental disease mechanisms.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Humans; Plaque, Amyloid; Protein Structure, Quaternary; Thermodynamics