Oligomerization of β-amyloid of the Alzheimer’s and the Dutch-cerebral-haemorrhage types

Sian, Aneet K.; Frears, Emma R.; El‐Agnaf, Omar M. A.; Patel, Bhroma P.; Manca, Maria Francesca; Siligardi, Giuliano; Hussain, Rohanah; Austen, Brian

doi:10.1042/0264-6021:3490299

Cited by 46 publications

(67 citation statements)

References 38 publications

(2 reference statements)

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“…3, we observed that oligomeric A␤-(1-42) inhibited neuronal viability ϳ10-fold more than fibrillar A␤-(1-42) (50% cell viability for oligomeric A␤-(1-42) Ϸ 0.4 M versus 4.0 M for fibrillar A␤-(1-42)), with significant oligomer toxicity exhibited as low as 10 nM. These results are particularly relevant when compared with previous publications that routinely required micromolar concentrations of A␤ to induce neurotoxicity (14,17,18,26,41,50).…”

Section: Resultsmentioning

confidence: 40%

“…These mutations induce an increase in the rate of fibril or protofibril formation in A␤- (1-40), respectively, without affecting the generation of A␤ or the A␤(1-42)/A␤(1-40) ratio and actually reduce A␤-(1-42) in transfected cells (31,38,41,42). The increase in protofibril and fibril formation of the mutants under the oligomerforming conditions did not induce a consistent change in neuronal viability.…”

Section: Resultsmentioning

confidence: 96%

“…Unlike mutations that increase either the total amount of A␤ or the ratio of A␤(1-42)/A␤(1-40), including the Flemish (A21G) mutation, the Dutch (E22Q) and Arctic (E22G) mutations actually reduce A␤-(1-42) levels in transfected cells and increase the formation of fibrils or protofibrils, respectively (31,38,41,42). Therefore, we utilized our A␤-(1-42) oligomer-and fibril-forming protocols to compare the structure and neurotoxicity of A␤-(1-42) with E22Q or E22G mutations to wild type peptide.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, the Dutch mutation is associated with an increased rate of fibrillization (43,44), and the Arctic mutation induces a significant increase in protofibril formation with no difference in fibrillization (31). In terms of toxicity, A␤-(1-40) with the Dutch mutation induced greater toxicity in vitro than wild type peptide (38,41,45). The effect of the Arctic mutation on A␤-induced neurotoxicity has not been reported as yet.…”

mentioning

confidence: 94%

“…In contrast, the 19 -25 region of the A␤ peptide is critical to several properties of the peptide (36), including proteolysis by ␣-secretase (33,37), aggregation (38,39), and neurotoxicity (40). The Dutch and Arctic mutations are of particular interest for investigating the effect of the A␤-(1-42) oligomer-and fibril-forming conditions on structure and neuronal viability, because these mutations appear to change the aggregation of the peptide in the absence of an increase in either the total amount of A␤ or the ratio of A␤( 41,42). Specifically, the Dutch mutation is associated with an increased rate of fibrillization (43,44), and the Arctic mutation induces a significant increase in protofibril formation with no difference in fibrillization (31).…”

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confidence: 99%

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Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability

Dahlgren

Manelli

Stine

et al. 2002

Journal of Biological Chemistry

1,341

1,288

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Genetic evidence predicts a causative role for amyloid-␤ (A␤) in Alzheimer's disease. Recent debate has focused on whether fibrils (amyloid) or soluble oligomers of A␤ are the active species that contribute to neurodegeneration and dementia. We developed two aggregation protocols for the consistent production of stable oligomeric or fibrillar preparations of A␤-(1-42). Here we report that oligomers inhibit neuronal viability 10-fold more than fibrils and ϳ40-fold more than unaggregated peptide, with oligomeric A␤-(1-42)-induced inhibition significant at 10 nM. Under A␤-(1-42) oligomer-and fibril-forming conditions, A␤-(1-40) remains predominantly as unassembled monomer and had significantly less effect on neuronal viability than preparations of A␤-(1-42). We applied the aggregation protocols developed for wild type A␤-(1-42) to A␤-(1-42) with the Dutch (E22Q) or Arctic (E22G) mutations. Oligomeric preparations of the mutations exhibited extensive protofibril and fibril formation, respectively, but were not consistently different from wild type A␤-(1-42) in terms of inhibition of neuronal viability. However, fibrillar preparations of the mutants appeared larger and induced significantly more inhibition of neuronal viability than wild type A␤-(1-42) fibril preparations. These data demonstrate that protocols developed to produce oligomeric and fibrillar A␤-(1-42) are useful in distinguishing the structural and functional differences between A␤-(1-42) and A␤-(1-40) and genetic mutations of A␤-(1-42). Amyloid-␤ (A␤)1 is derived by the proteolytic processing of amyloid precursor protein (APP), resulting in a peptide predominantly 40 or 42 amino acids in length. Mutations in APP and the presenilins that increase the amount of A␤-(1-42) cause AD (for review, see Ref. 1). Historically, the "amyloid cascade" hypothesis has defined the fibrillization of A␤ into amyloid deposits, a pathologic hallmark of AD, as a toxic gain of function (2). That A␤-(1-42) is more fibrillogenic than A␤-(1-40) fits well with this hypothesis. However, amyloid plaques do not always correlate in number, tempo, or distribution with neurodegeneration or clinical dementia. Thus, recent debate within the AD community has focused on whether fibrillar (amyloid) or soluble oligomers of A␤ are the active species of the peptide that ultimately cause the synaptic loss and dementia associated with AD (3-7). In vivo, small, stable oligomers of A␤-(1-42) have been isolated from brain, plasma, and cerebrospinal fluid (8 -10) and correlate with the severity of neurodegeneration in AD (11, 12). Thus, although genetic evidence predicts that A␤ is a causative factor in AD, the role of fibrillar and oligomeric A␤ in the pathogenesis of AD remains unclear.Initial in vitro studies suggested that A␤-induced neurotoxicity required the peptide to adopt a fibrillar aggregation state, with unaggregated peptide at low doses actually exhibiting neurotrophic effects (13)(14)(15)(16)(17)(18)). Recent studies demonstrate that non-fibrillar structures, including oligomers and ...

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Section: Resultsmentioning

confidence: 40%

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 99%

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Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability

Dahlgren

Manelli

Stine

et al. 2002

Journal of Biological Chemistry

1,341

1,288

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The use of Seldi ProteinChip? Arrays to monitor production of Alzheimer's ?-amyloid in transfected cells

Austen

Frears

Davies³

2000

J. Peptide Sci.

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Amyloid‐beta oligomerization in Alzheimer dementia versus high‐pathology controls

Esparza

Zhao

Cirrito³

et al. 2012

Annals of Neurology

255

228

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Objective While amyloid-beta (Aβ) peptide deposition into insoluble plaques is a pathological hallmark of Alzheimer’s disease, soluble oligomeric Aβ has been hypothesized to more directly underlie impaired learning and memory in dementia of the Alzheimer type. However, the lack of a sensitive, specific, and quantitative assay for Aβ oligomers has hampered rigorous tests of this hypothesis. Methods We developed a plate-based single molecule counting fluorescence immunoassay for oligomeric Aβ sensitive to low pg/ml concentrations of synthetic Aβ dimers using the same Aβ-specific monoclonal antibody to both capture and detect Aβ. The Aβ oligomer assay does not recognize monomeric Aβ, amyloid precursor protein, or other non-Aβ peptide oligomers. Results Aβ oligomers were detected in aqueous cortical lysates from patients with dementia of the Alzheimer type and non-demented patients with Aβ plaque pathology. However, Aβ oligomer concentrations in demented patients’ lysates were tightly correlated with Aβ plaque coverage (r=0.88), but this relationship was weaker in those from non-demented patients (r=0.30) despite equivalent Aβ plaque pathology. The ratio of Aβ oligomer levels to plaque density fully distinguished demented from non-demented patients, with no overlap between groups in this derived variable. Other Aβ and plaque measures did not distinguish demented from non-demented patients. Aβ oligomers were not detected in cerebrospinal fluid with this assay. Interpretation The results raise the intriguing hypothesis that the linkage between plaques and oligomers may be a key pathophysiological event underlying dementia of the Alzheimer type. This Aβ oligomer assay may be useful for many tests of the oligomer hypothesis.

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Oligomerization of β-amyloid of the Alzheimer’s and the Dutch-cerebral-haemorrhage types

Cited by 46 publications

References 38 publications

Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability

Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability

The use of Seldi ProteinChip? Arrays to monitor production of Alzheimer's ?-amyloid in transfected cells

Amyloid‐beta oligomerization in Alzheimer dementia versus high‐pathology controls

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