Formation of Dynamic Soluble Surfactant-induced Amyloid β Peptide Aggregation Intermediates

Abelein, Axel; Kaspersen, Jørn Døvling; Nielsen, Søren Achim; Jensen, Grethe Vestergaard; Christiansen, Gunna; Pedersen, Jan Skov; Danielsson, Jens; Otzen, Daniel E.; Gräslund, Astrid

doi:10.1074/jbc.m113.470450

Cited by 48 publications

(37 citation statements)

References 67 publications

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“…In earlier studies by others, 0.2% SDS was reported to induce globular aggregates of Aβ; moreover, no fibrils were detected by atomic force microscopy (34). Our findings are consistent with those of others, who found that SDS initially induced globular aggregates of Aβ, which later assembled spontaneously into fibrils (35).…”

Section: Discussionsupporting

confidence: 92%

Distinct synthetic Aβ prion strains producing different amyloid deposits in bigenic mice

Stöhr

Condello

Watts

et al. 2014

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

153

152

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An increasing number of studies continue to show that the amyloid β (Aβ) peptide adopts an alternative conformation and acquires transmissibility; hence, it becomes a prion. Here, we report on the attributes of two strains of Aβ prions formed from synthetic Aβ peptides composed of either 40 or 42 residues. Modifying the conditions for Aβ polymerization increased both the protease resistance and prion infectivity compared with an earlier study. Approximately 150 d after intracerebral inoculation, both synthetic Aβ40 and Aβ42 prions produced a sustained rise in the bioluminescence imaging signal in the brains of bigenic Tg(APP23: Gfap-luc) mice, indicative of astrocytic gliosis. Pathological investigations showed that synthetic Aβ40 prions produced amyloid plaques containing both Aβ40 and Aβ42 in the brains of inoculated bigenic mice, whereas synthetic Aβ42 prions stimulated the formation of smaller, more numerous plaques composed predominantly of Aβ42. Synthetic Aβ40 preparations consisted of long straight fibrils; in contrast, the Aβ42 fibrils were much shorter. Addition of 3.47 mM (0.1%) SDS to the polymerization reaction produced Aβ42 fibrils that were indistinguishable from Aβ40 fibrils produced in the absence or presence of SDS. Moreover, the Aβ amyloid plaques in the brains of bigenic mice inoculated with Aβ42 prions prepared in the presence of SDS were similar to those found in mice that received Aβ40 prions. From these results, we conclude that the composition of Aβ plaques depends on the conformation of the inoculated Aβ polymers, and thus, these inocula represent distinct synthetic Aβ prion strains.Alzheimer's disease | in vitro | neurodegenerative diseases

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Section: Discussionsupporting

confidence: 92%

Distinct synthetic Aβ prion strains producing different amyloid deposits in bigenic mice

Stöhr

Condello

Watts

et al. 2014

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

153

152

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“…In Aβ 40 the Zn 2+ ion is coordinated by four ligands, the histidines H6, H13, and H14 and the N-terminal D1 (15). Interaction between Zn 2+ and Aβ 40 causes NMR signal loss of the N-terminal residues (15,17), and these data suggest that NMR signal loss may be attributed to a chemical exchange process on an NMR intermediate time scale (18) as reported for similar exchanging systems (19)(20)(21).…”

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confidence: 52%

Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation

Abelein

Gräslund

Danielsson

2015

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

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107

154

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Metal ions have emerged to play a key role in the aggregation process of amyloid β (Aβ) peptide that is closely related to the pathogenesis of Alzheimer's disease. A detailed understanding of the underlying mechanistic process of peptide-metal interactions, however, has been challenging to obtain. By applying a combination of NMR relaxation dispersion and fluorescence kinetics methods we have investigated quantitatively the thermodynamic Aβ-Zn 2+ binding features as well as how Zn 2+ modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn 2+ effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc Aβ 40 aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn 2+ , the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn 2+ transiently binds to residues in the N terminus of the monomeric peptide. A thermodynamic analysis supports a model where the N terminus is folded around the Zn 2+ ion, forming a marginally stable, short-lived folded Aβ 40 species. This conformation is highly dynamic and only a few percent of the peptide molecules adopt this structure at any given time point. Our findings suggest that the folded Aβ 40 -Zn 2+ complex modulates the fibril ends, where elongation takes place, which efficiently retards fibril formation. In this conceptual framework we propose that zinc adopts the role of a minimal antiaggregation chaperone for Aβ 40 .Alzheimer's disease | amyloid beta peptide | aggregation kinetics | zinc ion interactions | NMR relaxation

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“…By using those animals in the present study, we also found that intracellular bA was decreased following both time intervals of CDK5 silencing treatment in contrast to extracellular bA plaques, APP processing, and bA1-40/ 1-42 production, which were decreased only with shortterm treatment. This result suggests that CDK5 knockdown is relevant in the reversion of bA protein levels and for intra-and extracellular b-amyloidosis in older 33 Tg-AD mice for a shorter treatment period, given that soluble bA (bA1-40) is also involved in the pathogenesis of AD (Haass and Selkoe, 2007;Benilova et al, 2012, Abelein et al, 2013. This finding also suggests that, in a mode independent of this histopathological hallmark, CDK5 reduction downregulates insoluble tau and improves learning and memory with long-term treatment despite the recovery of basal enzymatic activity at 1-year postinjection.…”

Section: Discussionmentioning

confidence: 95%

Cyclin‐Dependent kinase 5 targeting prevents β‐Amyloid aggregation involving glycogen synthase kinase 3β and phosphatases

Castro-Alvarez

Uribe-Arias

Cardona‐Gómez

2015

J of Neuroscience Research

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Inappropriate activation of CDK5 due to proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles, β-amyloid aggregation and chronic neurodegeneration. At 18 months of age, 3xTg-AD mice were sacrificed after either three weeks (short-term) or one year (long-term) of CDK5 knockdown. In short-term-treated animals, CDK5 knockdown reversed β-amyloid aggregation in the hippocampi via inhibitory phosphorylation of GSK3β Ser 9 and activation of phosphatase PP2A. In long-term-treated animals, CDK5 knockdown induced a persistent reduction in CDK5 and prevented β-amyloid aggregation, but the effect on APP processing was reduced, suggesting that yearly booster therapy would be necessary. These findings further validate CDK5 as a target for preventing or blocking amyloidosis in older transgenic mice.

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Formation of Dynamic Soluble Surfactant-induced Amyloid β Peptide Aggregation Intermediates

Cited by 48 publications

References 67 publications

Distinct synthetic Aβ prion strains producing different amyloid deposits in bigenic mice

Distinct synthetic Aβ prion strains producing different amyloid deposits in bigenic mice

Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation

Cyclin‐Dependent kinase 5 targeting prevents β‐Amyloid aggregation involving glycogen synthase kinase 3β and phosphatases

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