Pentapeptide Amides Interfere with the Aggregation of β-Amyloid Peptide of Alzheimer's Disease

Hetényi, Csaba; Szabó, Z. G.; Klement, Éva; Datki, Zsolt; Körtvélyesi, Tamás; M, Zarándi; Penke, Botond

doi:10.1006/bbrc.2002.6745

Cited by 60 publications

(45 citation statements)

References 30 publications

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“…To put this in context, previously considered inhibitors such as so-called ␤-sheet breaking peptides are typically effective only at much higher concentrations (32)(33)(34). Such a striking potency of the prion protein and its N-terminal fragments as inhibitors of the assembly of A␤ into toxic species may offer new avenues for pharmacological intervention in AD by using synthetic analogues/derivatives of these fragments.…”

Section: Resultsmentioning

confidence: 99%

Soluble Prion Protein Inhibits Amyloid-β (Aβ) Fibrillization and Toxicity

Nieznañski¹,

Choi

Chen

et al. 2012

Journal of Biological Chemistry

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Background: Prion protein was found to interact with A␤, but the consequences of this interaction are largely unknown. Results: Prion protein and its N-terminal fragment inhibit A␤1-42 amyloidogenesis and cytotoxicity. Conclusion: Soluble prion protein is a potent inhibitor of A␤1-42 assembly into toxic oligomers. Significance: The results have important implications for understanding the pathogenesis of AD and for the development of novel therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Soluble Prion Protein Inhibits Amyloid-β (Aβ) Fibrillization and Toxicity

Nieznañski¹,

Choi

Chen

et al. 2012

Journal of Biological Chemistry

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“…KLVFF-like peptide inhibitors (for a review, see Ref. 65) and inhibitors targeting the A␤ C terminus (66,67). The ability of a single amino acid substitution at the N terminus (Tyr 1 ) to alter the oligomer frequency distribution and the assembly kinetics suggests that the N terminus is not a benign peptide sub-region uninvolved in peptide assembly, as might be inferred from studies of fibril structure (68).…”

Section: Discussionmentioning

confidence: 99%

Amino Acid Position-specific Contributions to Amyloid β-Protein Oligomerization

Maji¹,

Loo

Inayathullah³

et al. 2009

Journal of Biological Chemistry

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Understanding the structural and assembly dynamics of the amyloid ␤-protein (A␤) has direct relevance to the development of therapeutic agents for Alzheimer disease. To elucidate these dynamics, we combined scanning amino acid substitution with a method for quantitative determination of the A␤ oligomer frequency distribution, photo-induced cross-linking of unmodified proteins (PICUP), to perform "scanning PICUP." Tyr, a reactive group in PICUP, was substituted at position 1, 10, 20, 30, or 40 (for A␤40) or 42 (for A␤42). The effects of these substitutions were probed using circular dichroism spectroscopy, thioflavin T binding, electron microscopy, PICUP, and mass spectrometry. All peptides displayed a random coil 3 ␣/␤ 3 ␤ transition, but substitution-dependent alterations in assembly kinetics and conformer complexity were observed. Tyr 1 -substituted homologues of A␤40 and A␤42 assembled the slowest and yielded unusual patterns of oligomer bands in gel electrophoresis experiments, suggesting oligomer compaction had occurred. Consistent with this suggestion was the observation of relatively narrow [Tyr 1 ]A␤40 fibrils. Substitution of A␤40 at the C terminus decreased the population conformational complexity and substantially extended the highest order of oligomers observed. This latter effect was observed in both A␤40 and A␤42 as the Tyr substitution position number increased. The ability of a single substitution (Tyr 1 ) to alter A␤ assembly kinetics and the oligomer frequency distribution suggests that the N terminus is not a benign peptide segment, but rather that A␤ conformational dynamics and assembly are affected significantly by the competition between the N and C termini to form a stable complex with the central hydrophobic cluster.Alzheimer disease (AD) 4 is the most common cause of latelife dementia (1) and is estimated to afflict more than 27 million people worldwide (2). An important etiologic hypothesis is that amyloid ␤-protein (A␤) oligomers are the proximate neurotoxins in AD. Substantial in vivo and in vitro evidence supports this hypothesis (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Neurotoxicity studies have shown that A␤ assemblies are potent neurotoxins (5,(13)(14)(15)(16)(17)(18)(19)(20), and the toxicity of some oligomers can be greater than that of the corresponding fibrils (21). Soluble A␤ oligomers inhibit hippocampal long term potentiation (4,5,13,15,17,18,22) and disrupt cognitive function (23). Compounds that bind and disrupt the formation of oligomers have been shown to block the neurotoxicity of A␤ (24,25). Importantly, recent studies in higher vertebrates (dogs) have shown that substantial reduction in amyloid deposits in the absence of decreases in oligomer concentration has little effect on recovery of neurological function (26).Recent studies of A␤ oligomers have sought to correlate oligomer size and biological activity. Oligomers in the supernatants of fibril preparations centrifuged at 100,000 ϫ g caused sustained calcium influx in rat hippocampal neurons, leading to calpain activati...

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“…31͒ and the ptraj module of AMBER9. In order to analyze the binding of certain inhibitor peptides with our final dimer configurations, we use the AUTODOCK4.0 program 32 and ClusPro server. 33 The interactions of the target peptides ␤ 1-27 , ␤ [29][30][31][32][33][34][35][36][37][38][39][40][41][42] , and A␤ 1-39 with the inhibitor peptides BSB-KLVFF, 34 LPFFD, 35 LVFFA, 36 and GVVIA 37 ͑here BSB stands for beta sheet breaker, and the other capital letters characterize the amino acid sequence of the peptides in the one-letter-code͒ are calculated and compared to the experimental results available. 34,36,37 The docking runs are performed using the Lamarckian genetic algorithm.…”

Section: Methodsmentioning

confidence: 99%

The Alzheimer β-amyloid (Aβ1–39) dimer in an implicit solvent

Anand

Nandel

Hansmann

2008

The Journal of Chemical Physics

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Oligomers of A␤ peptides are suspected as the underlying cause of Alzheimer disease. Knowledge of their structural properties could therefore lead to a deeper understanding of the mechanism behind the outbreak of this disease. As a step in this direction we have studied A␤ dimers by all-atom molecular dynamics simulations. Equilibrated structures at 300 K were clustered into different families with similar structural features. The dominant cluster has parallel N-terminals and a well defined segment Leu17-Ala21 that are stabilized by salt bridges between Lys28 of one chain and either Glu22 or Asp23 of the other chain. The formation of these salt bridges may be the limiting step in oligomerization and fibrillogenesis.

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Pentapeptide Amides Interfere with the Aggregation of β-Amyloid Peptide of Alzheimer's Disease

Cited by 60 publications

References 30 publications

Soluble Prion Protein Inhibits Amyloid-β (Aβ) Fibrillization and Toxicity

Soluble Prion Protein Inhibits Amyloid-β (Aβ) Fibrillization and Toxicity

Amino Acid Position-specific Contributions to Amyloid β-Protein Oligomerization

The Alzheimer β-amyloid (Aβ1–39) dimer in an implicit solvent

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