Inhibition of the accumulation of amyloid beta-peptide (Abeta) and the formation of beta-amyloid fibrils (fAbeta) from Abeta, as well as the destabilization of preformed fAbeta in the central nervous system, would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). We reported previously that nordihydroguaiaretic acid (NDGA) and wine-related polyphenols inhibit fAbeta formation from Abeta(1-40) and Abeta(1-42) and destabilize preformed fAbeta(1-40) and fAbeta(1-42) dose-dependently in vitro. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of curcumin (Cur) and rosmarinic acid (RA) on the formation, extension, and destabilization of fAbeta(1-40) and fAbeta(1-42) at pH 7.5 at 37 degrees C in vitro. We next compared the anti-amyloidogenic activities of Cur and RA with NDGA. Cur and RA dose-dependently inhibited fAbeta formation from Abeta(1-40) and Abeta(1-42), as well as their extension. In addition, they dose-dependently destabilized preformed fAbetas. The overall activities of Cur, RA, and NDGA were similar. The effective concentrations (EC(50)) of Cur, RA, and NDGA for the formation, extension, and destabilization of fAbetas were in the order of 0.1-1 microM. Although the mechanism by which Cur and RA inhibit fAbeta formation from Abeta and destabilize preformed fAbeta in vitro remains unclear, they could be a key molecule for the development of therapeutics for AD.

Curcumin has potent anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

Filamentous inclusions made of alpha-synuclein constitute the defining neuropathological characteristic of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Rare familial cases of Parkinson's disease are associated with mutations A53T and A30P in alpha-synuclein. We report here the assembly properties and secondary structure characteristics of recombinant alpha-synuclein. Carboxy-terminally truncated human alpha-synuclein (1-87) and (1-120) showed the fastest rates of assembly, followed by human A53T alpha-synuclein, and rat and zebra finch alpha-synuclein. Wild-type human alpha-synuclein and the A30P mutant showed slower rates of assembly. Upon shaking, filaments formed within 48 h at 37 degrees C. The related proteins beta- and gamma-synuclein only assembled after several weeks of incubation. Synthetic human alpha-synuclein filaments were decorated by an antibody directed against the carboxy-terminal 10 amino acids of alpha-synuclein, as were filaments extracted from dementia with Lewy bodies and multiple system atrophy brains. Circular dichroism spectroscopy indicated that alpha-synuclein undergoes a conformational change from random coil to beta-sheet structure during assembly. X-ray diffraction and electron diffraction of the alpha-synuclein assemblies showed a cross-beta conformation characteristic of amyloid.

https://www.pnas.org/content/pnas/97/9/4897.full.pdf

Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation.

https://escholarship.org/content/qt3ps1m1q5/qt3ps1m1q5.pdf?t=nu5hk2

Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis.

Cerebral deposition of amyloid beta-peptide (Abeta) in the brain is an invariant feature of Alzheimer's disease (AD). A consistent protective effect of wine consumption on AD has been documented by epidemiological studies. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of wine-related polyphenols (myricetin, morin, quercetin, kaempferol (+)-catechin and (-)-epicatechin) on the formation, extension, and destabilization of beta-amyloid fibrils (fAbeta) at pH 7.5 at 37 degrees C in vitro. All examined polyphenols dose-dependently inhibited formation of fAbeta from fresh Abeta(1-40) and Abeta(1-42), as well as their extension. Moreover, these polyphenols dose-dependently destabilized preformed fAbetas. The overall activity of the molecules examined was in the order of: myricetin = morin = quercetin > kaempferol > (+)-catechin = (-)-epicatechin. The effective concentrations (EC50) of myricetin, morin and quercetin for the formation, extension and destabilization of fAbetas were in the order of 0.1-1 micro m. In cell culture experiments, myricetin-treated fAbeta were suggested to be less toxic than intact fAbeta, as demonstrated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which these polyphenols inhibit fAbeta formation from Abeta, and destabilize pre-formed fAbetain vitro are still unclear, polyphenols could be a key molecule for the development of preventives and therapeutics for AD.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.2003.01976.x

Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease

The pathogenesis of Alzheimer's disease is characterized by the aggregation and fibrillation of the 40-residue Aβ(1−40) and 42-residue Aβ(1−42) peptides into amyloid plaques. The structural changes associated with the conversion of monomeric Aβ peptide building blocks into multimeric fibrillar β-strand aggregates remain unknown. Recently, we established that oxidation of the methionine-35 side chain to the sulfoxide (Met35red → Met35ox) significantly impedes the rate of aggregation and fibrillation of the Aβ peptide. To explore this effect at greater resolution, we carefully compared the 1H, 15N, and 13C NMR chemical shifts of four Aβ peptides that had the Met35 reduced or oxidized (Aβ(1−40)Met35red, Aβ(1−40)Met35ox, Aβ(1−42)Met35red, and Aβ(1−42)Met35ox). With the use of a special disaggregation protocol, the highly aggregation prone Aβ peptides could be studied at higher, millimolar concentrations (as required by NMR) in aqueous solution at neutral pH, remaining largely monomeric at 5 °C as determined b...

/pdf/solution-nmr-studies-of-the-ab-1-40-and-ab-1-42-peptides-52itdemu8t.pdf

Solution NMR Studies of the Aβ(1−40) and Aβ(1−42) Peptides Establish that the Met35 Oxidation State Affects the Mechanism of Amyloid Formation

Publisher Summary The immense difficulties and unexpected questions presented by hundreds of amyloid toxicity studies beg for a careful study of A β assembly processes, evaluating the kinetics and structures of different aggregation pathways that convert the soluble monomer into the higher order A β assemblies that harbor neurotoxic properties. A large array of sophisticated instrumental techniques, including analytical ultracentrifugation, atomic force microscopy, solid-state and solution NMR, and fluorescence tracer techniques, will help elucidate the bioactive A β structure(s), whereas specific cellular and biochemical techniques will elucidate the specific steps involved in the aftermath of A β cellular interactions. Nonetheless, all these potentially useful high technology methods are ineffective unless proper care regarding A β sample preparation is taken into account. This chapter briefly summarizes potential problems involved with A β sample preparation and has also described methods to deal with these issues. The most critical complications are related to the starting structures and aggregation states of the A β .

Methodological and chemical factors affecting amyloid beta peptide amyloidogenicity.

https://www.case.edu/artsci/chem/faculty/zagorski/group/pubs/pub45.pdf

Nicotine and amyloid formation

Amyloid AB (1–40) and AB(1–42) adopt remarkably stable, monomeric, and extended structures in water solution at neutral pH

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Methodological and chemical factors affecting amyloid beta peptide amyloidogenicity.

Nicotine and amyloid formation

Amyloid AB (1–40) and AB(1–42) adopt remarkably stable, monomeric, and extended structures in water solution at neutral pH