Two-hybrid system as a model to study the interaction of beta-amyloid peptide monomers.

Hughes, Stephen R.; Goyal, Shefali; Sun, Jeannie E.; Gonzalez-DeWhitt, Patricia A.; Fortes, Maryann; Riedel, Norbert G.; Sahasrabudhe, Sudhir

doi:10.1073/pnas.93.5.2065

Cited by 57 publications

(46 citation statements)

References 38 publications

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“…It is tempting to speculate that RO-47-1816/001, after it has bound to the amyloid fibril, binds to the soluble peptide and brings it into close proximity to the fibril (Fig. 8), thereby facilitating docking of the peptides via their specific binding sequences (20,21,36). Whether cross-linking is mediated directly by RO-47-1816/001 or by a composite surface of RO-47-1816/001 and the A␤ polymer is not clear.…”

Section: A␤ Ligands Structurally Related To Ro-47-1816/001mentioning

confidence: 99%

Controlling Polymerization of β-Amyloid and Prion-derived Peptides with Synthetic Small Molecule Ligands

Kuner¹,

Bohrmann²,

Tjernberg³

et al. 2000

Journal of Biological Chemistry

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The Alzheimer ␤-amyloid peptide (A␤) and a fragment of the prion protein have the capacity of forming amyloid-like fibrils when incubated under physiological conditions in vitro. Here we show that a small amyloid ligand, RO-47-1816/001, enhances this process severalfold by binding to amyloid molecules and apparently promote formation of the peptide-to-peptide bonds that join the monomers of the amyloid fibrils. This effect could be antagonized by other ligands, including analogues of RO-47-1816/001, as well as the structurally unrelated ligand Congo red. Analogues of RO-47-1816/001 with low affinity for amyloid did not display any antagonistic effect. In conclusion, these data suggest that synthetic molecules, and possibly also small natural substances present in the brain, may act in a chaperone-like fashion, promoting A␤ polymerization and growth of amyloid fibrils in vitro and possibly also in vivo. Furthermore, we demonstrate that small organic molecules can be used to inhibit the action of amyloid-enhancing compounds.The amyloid deposits in brain vasculature and parenchyma that are the main histopathological hallmarks of Alzheimer's disease (1) are composed of large polymers of Alzheimer ␤-amyloid peptide (A␤). 1 This peptide is present in two major forms, one being 40 amino acids long, and the other, more aggregable form being 42 amino acids long (2-4). The A␤ peptide is secreted by numerous cell types in the body but the amyloid deposits are only present in the central nervous system.The amyloid deposits are formed by the aggregation of individual monomers of A␤ peptide into very large polymers which have a fibril-like appearance when observed in an electron microscope (5). These polymers can also be observed by light microscopy following staining with certain histological dyes such as Congo red and thioflavine T (6).Soluble A␤ peptide can be detected in blood and cerebrospinal fluid. The levels are, however, very low, usually in the low nano-to picomolar range and at these concentrations the peptide polymerizes at a very slow rate (7). A number of recent studies on the mechanisms of amyloid formation have conclusively shown that the presence of preformed oligo-or polymers of the amyloid peptide in the reaction mixture increases the polymerization rate dramatically (7). These multimers serve as templates for the reaction and, as a result, the initial, slow phase of primary nucleation is eliminated.It has also been proposed that charged molecules, such as gangliosides (8) and metal ions, including Zn 2ϩ and Cu 2ϩ (9), may enhance formation of amyloid in vitro and in vivo. Apolipoprotein E4, a well established risk factor for Alzheimer's disease (10) has also been suggested to enhance amyloid formation by serving as a "pathological chaperone" (11-13). In the case of apolipoprotein E, there are conflicting data suggesting that the protein can enhance as well as inhibit amyloidogenesis (14, 15).The existence of putative co-factors capable of enhancing amyloid formation potentially offers new targets for pharm...

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Section: A␤ Ligands Structurally Related To Ro-47-1816/001mentioning

confidence: 99%

Controlling Polymerization of β-Amyloid and Prion-derived Peptides with Synthetic Small Molecule Ligands

Kuner¹,

Bohrmann²,

Tjernberg³

et al. 2000

Journal of Biological Chemistry

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“…Ab [16][17][18][19][20] binds to the homologous regions Ab [17][18][19][20][21] or Ab [18][19][20][21][22] and forms an antiparallel b-sheet structure [24][25][26][27]. The 21-30 region of Ab (Ab [21][22][23][24][25][26][27][28][29][30] ) is another important sequence involved in the aggregation process. The formation of b-turn structure in this region nucleates the folding process of Ab monomer, and initiates the molecular association to form oligomeric intermediates [28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Effect of N‐homocysteinylation on physicochemical and cytotoxic properties of amyloid β‐peptide

et al. 2011

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a b s t r a c tHyperhomocysteinemia has recently been identified as an important risk factor for Alzheimer's disease (AD). One of the potential mechanisms underlying harmful effects of homocysteine (Hcy) is site-specific acylation of proteins at lysine residues by homocysteine thiolactone (HCTL). The accumulation of amyloid b-peptide (Ab) in the brain is a neuropathological hallmark of AD. In the present study we were interested to investigate the effects of N-homocysteinylation on the aggregation propensity and neurotoxicity of Ab 1-42 . By coupling several techniques, we demonstrated that the homocysteinylation of lysine residues increase the neurotoxicity of the Ab peptide by stabilizing soluble oligomeric intermediates. Structured summary of protein interactions:A Beta 1-42 and A Beta 1-42 bind by fluorescence technology (View interaction) A Beta 1-42 and A Beta 1-42 bind by electron microscopy (View interaction)

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“…Совершенно очевидно, что эти подходы не по зволяют осуществлять масштабный скрининг аген тов, блокирующих формирование амилоидных тя жей. Сравнительно недавно было показано, что А β пептид человека способен образовывать агрега ты в дрожжевой клетке [12]. Дрожжи являются удобным модельным объектом для анализа факто ров, контролирующих процесс амилоидогенеза.…”

Section: Issn 1811 0932unclassified

ANALIZ EFFEKTOV PRODUKTsII GIBRIDNOGO BELKA Aβ-SUP35MC V DROZhZhAKh SACCHAROMYCES CEREVISIAE

Tsaponina¹,

Лада²,

Rubel³

et al. 2005

Ecological genetics

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Two-hybrid system as a model to study the interaction of beta-amyloid peptide monomers.

Abstract: The kinetics of amyloid fibril formation by f3-amyloid peptide (A18) are typical of a nucleation-dependent polymerization mechanism.

Cited by 57 publications

References 38 publications

Controlling Polymerization of β-Amyloid and Prion-derived Peptides with Synthetic Small Molecule Ligands

Controlling Polymerization of β-Amyloid and Prion-derived Peptides with Synthetic Small Molecule Ligands

Effect of N‐homocysteinylation on physicochemical and cytotoxic properties of amyloid β‐peptide

ANALIZ EFFEKTOV PRODUKTsII GIBRIDNOGO BELKA Aβ-SUP35MC V DROZhZhAKh SACCHAROMYCES CEREVISIAE

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