Characterization of the Amyloid Fibril as a Cross-  Protein

Bonar, Laurence C.; Cohen, Alan S.; Skinner, Martha M.

doi:10.3181/00379727-131-34110

Cited by 161 publications

(91 citation statements)

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“…3A, TABFOs produce broad diffraction peaks at 4.7 and ∼10 Å. Although the TABFOs are not oriented in this experiment, these peaks are consistent with a spherically averaged cross-β pattern (15)(16)(17). This pattern does not arise from the presence of mature amyloid fibers, because EM micrographs of these oligomers do not reveal mature fibers (Fig.…”

Section: Resultsmentioning

confidence: 53%

“…Fiber diffraction studies of chemically pure amyloid display a cross-β diffraction pattern that includes a 4.7 Å meridional reflection (parallel to the fiber direction) and an ∼10 Å equatorial reflection (perpendicular to the fiber direction) (15,16). The meridional reflection arises from the hydrogen-bonded stacking of β-strands perpendicular to the fiber axis.…”

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confidence: 99%

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Toxic fibrillar oligomers of amyloid-β have cross-β structure

Stroud

Liu

Teng

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

301

273

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Although amyloid fibers are found in neurodegenerative diseases, evidence points to soluble oligomers of amyloid-forming proteins as the cytotoxic species. Here, we establish that our preparation of toxic amyloid-β 1-42 (Abeta42) fibrillar oligomers (TABFOs) shares with mature amyloid fibrils the cross-β structure, in which adjacent β-sheets adhere by interpenetration of protein side chains. We study the structure and properties of TABFOs by powder X-ray diffraction, EM, circular dichroism, FTIR spectroscopy, chromatography, conformational antibodies, and celluar toxicity. In TABFOs, Abeta42 molecules stack into short protofilaments consisting of pairs of helical β-sheets that wrap around each other to form a superhelix. Wrapping results in a hole along the superhelix axis, providing insight into how Abeta may form pathogenic amyloid pores. Our model is consistent with numerous properties of Abeta42 fibrillar oligomers, including heterogenous size, ability to seed new populations of fibrillar oligomers, and fiber-like morphology.Abeta oligomers | toxic oligomers | Alzheimer's disease | domain swapping | protein aggregation S everal neurodegenerative diseases are correlated with amyloid fibrillar deposits (1). For a number of these diseases, it has been postulated that amyloid fibers may not play the primary causative role (2). Rather, soluble aggregates of the amyloidogenic proteins are likely the relevant etiological agents (2, 3). The most prevalent of these neurodegenerative diseases, Alzheimer's disease (4), is strongly linked to the presence of soluble aggregates of amyloid-β (Abeta) (5). Abeta aggregates have been shown to impair neurite function (6), synaptic morphology (7), cognitive function (8), and cell viability (9). In the prion conditions, also classed as amyloid diseases (10), small oligomers have also been identified as the toxic species (11). Recently, the availability of structure-specific antibodies has provided a means to group oligomers into two broad antigenic categories known as prefibrillar and fibrillar oligomers (12). Fibrillar oligomers are recognized by the OC antibody isolated from rabbits immunized with Abeta fibers (13), suggesting that Abeta fibrillar oligomers share surface features with Abeta fibers. In addition to fiber-like morphology, fibrillar oligomers are similar to fibers in that fibrillar oligomers can seed new populations of fibrillar oligomers (14). The ability to seed suggests that, like fibers, fibrillar oligomers are organized into a repeating array or lattice of monomers, wherein the monomers have identical structures. Fibrillar oligomers likely have a distinct lattice from fibers, because Abeta fibrillar oligomers do not seed Abeta fiber formation (14). Here, we characterize a particular preparation of fibrillar oligomers that we term toxic Abeta 1-42 (Abeta42) fibrillar oligomers (TABFOs).The structure of amyloid fibers may provide insight into the structure of fibrillar oligomers. Fiber diffraction studies of chemically pure amyloid display a cross-β diffraction...

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Section: Resultsmentioning

confidence: 53%

mentioning

confidence: 99%

Toxic fibrillar oligomers of amyloid-β have cross-β structure

Stroud

Liu

Teng

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

301

273

View full text Add to dashboard Cite

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“…These so-called amyloid diseases are named after the cross-β-sheet aggregates, or amyloid fibrils, that are the pathological hallmarks of these maladies. (212,213) Amyloid fibrils in a specific disease are generally composed predominantly of one protein5. Amyloid fibrils from different diseases and composed of different proteins exhibit similar structural features.…”

Section: Mitochondrial -Lysosomal Dysfunction In Nddmentioning

confidence: 99%

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

2018

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B ACKGROUND:Redox and proteotoxic stress contributes to age-dependent accumulation of dysfunctional mitochondria and protein aggregates, and is associated with neurodegeneration. The free radical theory of aging inspired many studies using reactive species scavengers such as alpha-tocopherol, ascorbate and coenzyme-Q to suppress the initiation of oxidative stress. However, clinical trials have had limited success in the treatment of neurodegenerative diseases (NDDs). CONTENT:The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of NDDs. In Alzheimer's disease, the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism, corruptive protein templating. The accumulation of redox modified proteins or organelles cannot be reversed by oxidant intercepting antioxidants and must then be removed by alternative mechanisms. Autophagy serves this essential function in removing damaged or dysfunctional proteins and organelles thus preserving neuronal function and survival.SUMMARY: Senescent cells and their senescenceassociated secretory phenotypes (SASPs) may constitute a novel, understudied, and potentially important contributor to neuro-inflammation and subsequent neurodegeneration. Characterization of cellular senescence in the brain could uncover novel therapeutic targets for the prevention and treatment of chronic age-related NDDs. KEYwORDS

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“…The accumulation of amyloid in one or more visceral organs such as heart, kidney, liver, gastrointestinal tract and lungs characteristically results in progressive organ failure and, eventually, in death of the patient (1)(2)(3). Treatment of AL with chemotherapeutic agents has been associated with only modest improvement in median survival (4)(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…Primary systemic amyloidosis (AL) is a plasma cell dyscrasia characterized by the production of monoclonal light chain fragments capable of forming beta-pleated sheets that are deposited in multiple soft tissues (1)(2)(3). The accumulation of amyloid in one or more visceral organs such as heart, kidney, liver, gastrointestinal tract and lungs characteristically results in progressive organ failure and, eventually, in death of the patient (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%