Neurotoxic protein oligomers — what you see is not always what you get

Bitan, Gal; Fradinger, Erica A.; Spring, Sean; Teplow, David B.

doi:10.1080/13506120500106958

Cited by 208 publications

(225 citation statements)

References 76 publications

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“…The initial and final states of Ab fibrillogenesis have been well established and characterized by biophysical methods [26,27,40,41], but conversely, the dynamic process leading to aggregation and to the formation of oligomeric intermediates is much less understood and still under investigation [24,42]. Tycko's group provided evidence for a parallel b-sheet organization in the fibrils using solid state NMR implicating residues 12-40 with a turn located around residues 21-30 [25,26,41].…”

Section: Discussionmentioning

confidence: 99%

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

135

119

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Alzheimer's disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid beta peptide (Ab) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared spectroscopy to provide structural information on the entire aggregation pathway of Ab(1-40), starting from monomeric Ab to the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition from antiparallel to parallel b-sheet. These structural changes are described in terms of H-bonding rupture/formation, b-strands reorientation and b-sheet elongation. As antiparallel b-sheet structure is also observed for other amyloidogenic proteins forming oligomers, reorganization of the b-sheet implicating a reorientation of b-strands could be a generic mechanism determining the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could be essential in a search for therapies inhibiting aggregation or disrupting aggregates.

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Section: Discussionmentioning

confidence: 99%

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

135

119

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“…1b). Previous studies have suggested that this anomalous migration of Aβ42 on SDS gels is a result of SDS-induced Aβ oligomerization because of the effect of SDS micelle formation and high local concentration of Aβ in micelles 73 . In addition, it is also possible that Aβ42 at higher than critical concentrations, and because of its high aggregation tendency, exists in equilibrium with LMW oligomers (dimers, trimers and low n-mers) seen on the gels 53,73 .…”

Section: |mentioning

confidence: 93%

“…To prepare monomeric Aβ fractions, the lyophilized peptide is dissolved and disaggregated by guanidine hydrochloride treatment 65,73 , and then the solution is injected into a suitable SEC column to separate Aβ monomers from guanidine ( Table 2).…”

Section: Experimental Designmentioning

confidence: 99%

“…Previous translational diffusion measurements of these Aβ elution fractions, by pulse field gradient solution phase NMR, showed that Aβ predominantly elutes as a monomer 80 . The presence of a small amount of LMW oligomers (dimers, trimers, and so on), which exist in rapid equilibrium with the monomer, has been suggested and cannot be ruled out 53,73 . However, these oligomeric species do not seem to accumulate or exist in stable forms, unless stabilized by chemical crosslinking 17 .…”

Section: |mentioning

confidence: 99%

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Preparation and characterization of toxic Aβ aggregates for structural and functional studies in Alzheimer's disease research

2010

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“…In recent years, accumulating evidence has indicated that soluble amyloid assemblies rather than the mature amyloid plaques may actually be the pathological culprits that result in the degenerative phenomena ( Figure 1) (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

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confidence: 99%

From Green Bacteria to Human Dementia: A Novel Model for Discovering Amyloid Assembly Inhibitors

Gazit

2006

ACS Chem. Biol.

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he formation of amyloid assemblies, which are large protein aggregates that share biophysical, biochemical, and ultrastructural properties, is associated with Ͼ20 human disorders (1, 2). Despite the amyloid-forming proteins' different origins and the lack of any simple homology among them, in all cases fine 7-10 nm fibrils are observed that have a predominant ␤-sheet structure and a strong birefringence upon staining with Congo red. One of the most notable properties of amyloid fibrils is their effect on the fluorescence of small aromatic dyes such as thioflavin. When the dye binds to mature amyloid fibrils, its fluorescence markedly increases. Therefore, the ability to inhibit amyloid fibril formation, as reflected by the thioflavin fluorescence, is based on the use of a major assay for the high-throughput screening of inhibitors.Amyloid fibril formation has been associated with some of the most common and grave degenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and type 2 diabetes. However, despite continuous efforts by academic groups and the pharmaceutical industry, currently no approved therapeutic agents can control the process of amyloid formation and reverse the degenerative symptoms observed in these disorders. Despite the screening of large chemical libraries that may contain hundreds or thousands of compounds that use the thioflavin assay, as mentioned above, no direct amyloid

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Neurotoxic protein oligomers — what you see is not always what you get

Cited by 208 publications

References 76 publications

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Preparation and characterization of toxic Aβ aggregates for structural and functional studies in Alzheimer's disease research

From Green Bacteria to Human Dementia: A Novel Model for Discovering Amyloid Assembly Inhibitors

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