Small Molecule Inhibitors of Aggregation Indicate That Amyloid β Oligomerization and Fibrillization Pathways Are Independent and Distinct
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TLDR
The results indicate that oligomers are not an obligate intermediate in the fibril formation pathway and 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.About:
This article is published in Journal of Biological Chemistry.The article was published on 2007-04-06 and is currently open access. It has received 705 citations till now. The article focuses on the topics: Protein aggregation & Fibril.read more
Citations
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New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
TL;DR: A number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens are described.
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The amyloid state of proteins in human diseases
TL;DR: This work summarizes studies of structure and nucleation of amyloid and relate these to observations on amyloids polymorphism, prion strains, coaggregation of pathogenic proteins in tissues, and mechanisms of toxicity and transmissibility.
Journal ArticleDOI
Alzheimer's Disease and the Amyloid-β Peptide
M. Paul Murphy,Harry LeVine +1 more
TL;DR: Interestingly, deposited Abeta in AD is different from that found in animal models and does not show the same physical and biochemical characteristics as the amyloid found in AD, which raises important issues regarding the development and testing of future therapeutic agents.
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Structural classification of toxic amyloid oligomers.
TL;DR: Conformation-dependent antibodies that recognize generic epitopes that are specifically associated with distinct aggregation states of many different amyloid-forming sequences indicate that there are at least two fundamentally distinct types of amyloidal oligomers: fibrillar and prefibrilar oligomers.
Journal ArticleDOI
The amyloid beta peptide: a chemist's perspective. Role in Alzheimer's and fibrillization.
TL;DR: The γ-secretase complex and its cell surface localization, in the absence of an effect on Notch, is studied to avoid side-effects caused by EP2 receptor.
References
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The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics
John Hardy,Dennis J. Selkoe +1 more
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
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Protein folding and misfolding
TL;DR: The manner in which a newly synthesized chain of amino acids transforms itself into a perfectly folded protein depends both on the intrinsic properties of the amino-acid sequence and on multiple contributing influences from the crowded cellular milieu.
Journal ArticleDOI
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis
Rakez Kayed,Elizabeth Head,Jennifer L. Thompson,Theresa M. McIntire,Saskia Milton,Carl W. Cotman,Charles G. Glabe +6 more
TL;DR: It is shown that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomer regardless of sequence, suggesting they share a common mechanism of toxicity.
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Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins
Mary P. Lambert,A. K. Barlow,Brett A. Chromy,C. Edwards,R. Freed,M. Liosatos,Todd E. Morgan,Irina Rozovsky,Barbara L. Trommer,Kirsten L. Viola,Pat Wals,Chuan Zhang,Caleb E. Finch,Grant A. Krafft,William L. Klein +14 more
TL;DR: It is hypothesized that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways.
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A specific amyloid-|[beta]| protein assembly in the brain impairs memory
Sylvain Lesné,Ming Teng Koh,Linda Kotilinek,Rakez Kayed,Charles G. Glabe,Austin J. Yang,Michela Gallagher,Karen H. Ashe +7 more
TL;DR: It is found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-β assembly, which is proposed to be Aβ*56 (Aβ star 56), which may contribute to cognitive deficits associated with Alzheimer's disease.
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