Structural Basis of β‐Amyloid‐Dependent Synaptic Dysfunctions

Haupt, Christian; Leppert, Jörg; Rönicke, Raik; Meinhardt, Jessica; Yadav, Jay Kant; Ramachandran, Ramadurai; Ohlenschläger, Oliver; Reymann, Klaus G.; Görlach, Matthias; Fändrich, Marcus

doi:10.1002/ange.201105638

Cited by 22 publications

(46 citation statements)

References 27 publications

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“…We propose that this more extended conformation of the N-terminal region of Aβ may form the structural basis for the enhanced stability of phosphorylated Aβ oligomers. This is in agreement with a recent report showing that the disruption of local extended conformation through S8P mutagenesis leads to selective destabilization of Aβ oligomers 37 .…”

Section: Discussionsupporting

confidence: 94%

“…Several lines of evidence attribute an important role for aggregation of Aβ to its N-terminal region 37 38 39 40 . The results from our MD simulation suggested that the high capacity of phosphate groups to act both as the donor and acceptor of hydrogen bonds can lead to the formation of a rich network of hydrogen bonds in the N-terminal region and significantly diminishes backbone dynamics in phosphorylated Aβ aggregates ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation modifies the molecular stability of β-amyloid deposits

et al. 2016

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Protein aggregation plays a crucial role in neurodegenerative diseases. A key feature of protein aggregates is their ubiquitous modification by phosphorylation. Little is known, however, about the molecular consequences of phosphorylation of protein aggregates. Here we show that phosphorylation of β-amyloid at serine 8 increases the stability of its pathogenic aggregates against high-pressure and SDS-induced dissociation. We further demonstrate that phosphorylation results in an elevated number of hydrogen bonds at the N terminus of β-amyloid, the region that is critically regulated by a variety of post-translational modifications. Because of the increased lifetime of phosphorylated β-amyloid aggregates, phosphorylation can promote the spreading of β-amyloid in Alzheimer pathogenesis. Our study suggests that regulation of the molecular stability of protein aggregates by post-translational modifications is a crucial factor for disease progression in the brain.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Phosphorylation modifies the molecular stability of β-amyloid deposits

et al. 2016

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“…The N‐terminal region of Aβ peptides is highly important for its aggregation and toxicity . We therefore decided to investigate the impact of N‐terminal elongation on the aggregation behavior of Aβ peptides using a set of biophysical techniques.…”

Section: Resultsmentioning

confidence: 99%

Solid‐Phase Synthesis and Characterization of N‐Terminally Elongated Aβ_−3–x‐Peptides

Beyer

Rezaei‐Ghaleh

Klafki

et al. 2016

Chemistry A European J

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In addition to the prototypic amyloid‐β (Aβ) peptides Aβ1–40 and Aβ1–42, several Aβ variants differing in their amino and carboxy termini have been described. Synthetic availability of an Aβ variant is often the key to study its role under physiological or pathological conditions. Herein, we report a protocol for the efficient solid‐phase peptide synthesis of the N‐terminally elongated Aβ‐peptides Aβ−3–38, Aβ−3–40, and Aβ−3–42. Biophysical characterization by NMR spectroscopy, CD spectroscopy, an aggregation assay, and electron microscopy revealed that all three peptides were prone to aggregation into amyloid fibrils. Immunoprecipitation, followed by mass spectrometry, indicated that Aβ−3–38 and Aβ−3–40 are generated by transfected cells even in the presence of a tripartite β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. The elongated Aβ peptides starting at Val(−3) can be separated from N‐terminally‐truncated Aβ forms by high‐resolution isoelectric‐focusing techniques, despite virtually identical isoelectric points. The synthetic Aβ variants and the methods presented here are providing tools to advance our understanding of the potential roles of N‐terminally elongated Aβ variants in Alzheimer's disease.

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“…The finding that KW1 expression specifically affects Aβ(1-40)-transgenic animals was highly surprising, given that it had previously been shown to antagonize Aβ(1-40) oligomer induced neurotoxicity (Figure 5A,B), as measured by the ability of preformed oligomers of Aβ(1-40) to disrupt synaptic plasticity and LTP in cultured murine brain slices [29,37,46]. An obvious contrast between the fly model described here, and previous in vitro work is that KW1 is produced in the brain of the fly concomitantly with Aβ(1-40) peptide and is present during fibril or oligomer formation (Figure 5C).…”

Section: Resultsmentioning

confidence: 99%

“…Fibrils were formed in vitro by incubation of pure peptide at 1 mg/ml concentration in 50 mM sodium borate buffer, pH 9.0, for 5 days at room temperature. Oligomers were prepared by dissolving pure peptide at 2.5 mg/ml concentration in 100% 1,1,1,3,3,3-hexafluoro-2-propanol [37]. After incubation for 15 min at room temperature, the solution was diluted 10-fold with H 2 O and further incubated for 15 min.…”

Section: Methodsmentioning

confidence: 99%

Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies

Wacker

Rönicke

Westermann

et al. 2014

acta neuropathol commun

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IntroductionThe self-assembly of Aβ peptides into a range of conformationally heterogeneous amyloid states represents a fundamental event in Alzheimer’s disease. Within these structures oligomeric intermediates are considered to be particularly pathogenic. To test this hypothesis we have used a conformational targeting approach where particular conformational states, such as oligomers or fibrils, are recognized in vivo by state-specific antibody fragments.ResultsWe show that oligomer targeting with the KW1 antibody fragment, but not fibril targeting with the B10 antibody fragment, affects toxicity in Aβ-expressing Drosophila melanogaster. The effect of KW1 is observed to occur selectively with flies expressing Aβ(1–40) and not with those expressing Aβ(1–42) or the arctic variant of Aβ(1–42) This finding is consistent with the binding preference of KW1 for Aβ(1–40) oligomers that has been established in vitro. Strikingly, and in contrast to the previously demonstrated in vitro ability of this antibody fragment to block oligomeric toxicity in long-term potentiation measurements, KW1 promotes toxicity in the flies rather than preventing it. This result shows the crucial importance of the environment in determining the influence of antibody binding on the nature and consequences of the protein misfolding and aggregation.ConclusionsWhile our data support to the pathological relevance of oligomers, they highlight the issues to be addressed when developing inhibitory strategies that aim to neutralize these states by means of antagonistic binding agents.

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Structural Basis of β‐Amyloid‐Dependent Synaptic Dysfunctions

Cited by 22 publications

References 27 publications

Phosphorylation modifies the molecular stability of β-amyloid deposits

Phosphorylation modifies the molecular stability of β-amyloid deposits

Solid‐Phase Synthesis and Characterization of N‐Terminally Elongated Aβ_−3–x‐Peptides

Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies

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Structural Basis of β‐Amyloid‐Dependent Synaptic Dysfunctions

Cited by 22 publications

References 27 publications

Phosphorylation modifies the molecular stability of β-amyloid deposits

Phosphorylation modifies the molecular stability of β-amyloid deposits

Solid‐Phase Synthesis and Characterization of N‐Terminally Elongated Aβ−3–x‐Peptides

Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies

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Product

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Solid‐Phase Synthesis and Characterization of N‐Terminally Elongated Aβ_−3–x‐Peptides