Dataset Information

Somatostatin binds to the human amyloid ? peptide and favors the formation of distinct oligomers.

ABSTRACT: The amyloid ? peptide (A?) is a key player in the etiology of Alzheimer disease (AD), yet a systematic investigation of its molecular interactions has not been reported. Here we identified by quantitative mass spectrometry proteins in human brain extract that bind to oligomeric A?1-42 (oA?1-42) and/or monomeric A?1-42 (mA?1-42) baits. Remarkably, the cyclic neuroendocrine peptide somatostatin-14 (SST14) was observed to be the most selectively enriched oA?1-42 binder. The binding interface comprises a central tryptophan within SST14 and the N-terminus of A?1-42. The presence of SST14 inhibited A? aggregation and masked the ability of several antibodies to detect A?. Notably, A?1-42, but not A?1-40, formed in the presence of SST14 oligomeric assemblies of 50 to 60 kDa that were visualized by gel electrophoresis, nanoparticle tracking analysis and electron microscopy. These findings may be relevant for A?-directed diagnostics and may signify a role of SST14 in the etiology of AD.

SUBMITTER: Wang H

PROVIDER: S-EPMC5505701 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers.

Wang Hansen H Muiznieks Lisa D LD Ghosh Punam P Williams Declan D Solarski Michael M Fang Andrew A Ruiz-Riquelme Alejandro A Pomès Régis R Watts Joel C JC Chakrabartty Avi A Wille Holger H Sharpe Simon S Schmitt-Ulms Gerold G

eLife 20170626

The amyloid β peptide (Aβ) is a key player in the etiology of Alzheimer disease (AD), yet a systematic investigation of its molecular interactions has not been reported. Here we identified by quantitative mass spectrometry proteins in human brain extract that bind to oligomeric Aβ1-42 (oAβ1-42) and/or monomeric Aβ1-42 (mAβ1-42) baits. Remarkably, the cyclic neuroendocrine peptide somatostatin-14 (SST14) was observed to be the most selectively enriched oAβ1-42 binder. The binding interface compri ...[more]

PMID: 28650319

Similar Datasets

Project description:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-? peptide (A?). Monomeric soluble A? can switch from helicoidal to ?-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. A? can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that A? nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an A? analog containing a single residue (H to E) replacement that mimics the behavior of nitrated A? related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated A? oligomers was observed. Our results show that A? nitrotyrosination is a post-translational modification that increases A? synaptotoxicity. SIGNIFICANCE STATEMENT:We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-? (A?) favors the stabilization of highly toxic oligomers and inhibits the formation of A? fibrils. The nitrated A? oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.

Dataset Information

Somatostatin binds to the human amyloid ? peptide and favors the formation of distinct oligomers.

Publications

Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets