Single-molecule probing of amyloid nano-ensembles using the polymer nanoarray approach.

Soluble amyloid-beta (Aβ) oligomers are the prime causative agents of cognitive deficits during early stages of Alzheimer's disease (AD). The transient nature of the oligomers makes them difficult to characterize by traditional techniques, suggesting that advanced approaches are necessary. Previously developed fluorescence-based tethered approach for probing intermolecular interactions (TAPIN) and AFM-based single-molecule force spectroscopy are capable of probing dimers of Aβ peptides. In this paper, a novel polymer nanoarray approach to probe trimers and tetramers formed by the Aβ(14-23) segment of Aβ protein at the single-molecule level is applied. By using this approach combined with TAPIN and AFM force spectroscopy, the impact of pH on the assembly of these oligomers was characterized. Experimental results reveal that pH affects the oligomer assembly process. At neutral pH, trimers and tetramers assemble into structures with a similar stability, while at acidic conditions (pH 3.7), the oligomers adopt a set of structures with different lifetimes and strengths. Models for the assembly of Aβ(14-23) trimers and tetramers based on the results obtained is proposed.

[1]  Y. Lyubchenko,et al.  Nano-assembly of amyloid β peptide: role of the hairpin fold , 2017, Scientific Reports.

[2]  Y. Lyubchenko,et al.  Effect of acidic pH on the stability of α‐synuclein dimers , 2016, Biopolymers.

[3]  Sara Linse,et al.  Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils. , 2016, Journal of the American Chemical Society.

[4]  C. Sigurdson,et al.  Polymorphism of Amyloid Fibrils In Vivo. , 2016, Angewandte Chemie.

[5]  Y. Lyubchenko,et al.  Probing of Amyloid Aβ (14-23) Trimers by Single-Molecule Force Spectroscopy. , 2016, Jacobs journal of molecular and translational medicine.

[6]  R. Cappai,et al.  Membrane‐bound tetramer and trimer Aβ oligomeric species correlate with toxicity towards cultured neurons , 2016, Journal of neurochemistry.

[7]  M. Woodside,et al.  Protein misfolding occurs by slow diffusion across multiple barriers in a rough energy landscape , 2015, Proceedings of the National Academy of Sciences.

[8]  Y. Lyubchenko.  Amyloid misfolding, aggregation, and the early onset of protein deposition diseases: insights from AFM experiments and computational analyses , 2015, AIMS molecular science.

[9]  Y. Lyubchenko,et al.  A flexible nanoarray approach for the assembly and probing of molecular complexes. , 2015, Biophysical journal.

[10]  Y. Lyubchenko,et al.  Direct Detection of α-Synuclein Dimerization Dynamics: Single-Molecule Fluorescence Analysis. , 2015, Biophysical journal.

[11]  S. Radford,et al.  pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers , 2015, Proceedings of the National Academy of Sciences.

[12]  Y. Lyubchenko,et al.  Role of monomer arrangement in the amyloid self-assembly. , 2015, Biochimica et biophysica acta.

[13]  Y. Lyubchenko,et al.  The structure of misfolded amyloidogenic dimers: computational analysis of force spectroscopy data. , 2014, Biophysical journal.

[14]  A. Olofsson,et al.  The N-terminal region of amyloid β controls the aggregation rate and fibril stability at low pH through a gain of function mechanism. , 2014, Journal of the American Chemical Society.

[15]  B. Schuler,et al.  Single-molecule studies of intrinsically disordered proteins. , 2014, Chemical reviews.

[16]  Y. Lyubchenko,et al.  α-Synuclein misfolding assessed with single molecule AFM force spectroscopy: effect of pathogenic mutations. , 2013, Biochemistry.

[17]  Y. Lyubchenko,et al.  Mechanism of amyloid β−protein dimerization determined using single−molecule AFM force spectroscopy , 2013, Scientific Reports.

[18]  Y. Lyubchenko,et al.  Molecular mechanism of misfolding and aggregation of Aβ(13-23). , 2013, The journal of physical chemistry. B.

[19]  P. Derreumaux,et al.  Intrinsic Determinants of Aβ 12–24 pH-Dependent Self-Assembly Revealed by Combined Computational and Experimental Studies , 2011, PloS one.

[20]  Nicholas Y. Palermo,et al.  Single-molecule atomic force microscopy force spectroscopy study of Aβ-40 interactions. , 2011, Biochemistry.

[21]  Y. Lyubchenko,et al.  Nanoimaging for protein misfolding diseases. , 2010, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[22]  E. Capetillo-Zarate,et al.  Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease , 2010, Acta Neuropathologica.

[23]  A. Surguchov,et al.  Conformational diseases: Looking into the eyes , 2010, Brain Research Bulletin.

[24]  N. Grigorieff,et al.  Nanoscale Flexibility Parameters of Alzheimer Amyloid Fibrils Determined by Electron Cryo-Microscopy** , 2010, Angewandte Chemie.

[25]  Richard W. Clarke,et al.  Direct characterization of amyloidogenic oligomers by single-molecule fluorescence , 2008, Proceedings of the National Academy of Sciences.

[26]  D. Selkoe,et al.  Aβ Oligomers – a decade of discovery , 2007, Journal of neurochemistry.

[27]  R. Tycko,et al.  Molecular Alignment within β-Sheets in Aβ14-23 Fibrils: Solid-State NMR Experiments and Theoretical Predictions , 2007 .

[28]  C. Dobson,et al.  Protein misfolding, functional amyloid, and human disease. , 2006, Annual review of biochemistry.

[29]  J. Trojanowski,et al.  Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. , 2006, Annual review of pathology.

[30]  Y. Lyubchenko,et al.  Protein interactions and misfolding analyzed by AFM force spectroscopy. , 2005, Journal of molecular biology.

[31]  J. D. McGaugh,et al.  Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice , 2005, Neuron.

[32]  S. Pasternak,et al.  The role of the endosomal/lysosomal system in amyloid-beta production and the pathophysiology of Alzheimer's disease: reexamining the spatial paradox from a lysosomal perspective. , 2003, Journal of Alzheimer's disease : JAD.

[33]  Yeu Su,et al.  Acidic pH promotes the formation of toxic fibrils from β-amyloid peptide , 2001, Brain Research.

[34]  L. Serpell,et al.  Alzheimer's amyloid fibrils: structure and assembly. , 2000, Biochimica et biophysica acta.

[35]  Lars Terenius,et al.  A Molecular Model of Alzheimer Amyloid β-Peptide Fibril Formation* , 1999, The Journal of Biological Chemistry.

[36]  A. Yang,et al.  Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid Aβ1‐42 pathogenesis , 1998, Journal of neuroscience research.

[37]  Y. Lyubchenko,et al.  Mica functionalization for imaging of DNA and protein-DNA complexes with atomic force microscopy. , 2013, Methods in molecular biology.

[38]  Michelle D. Wang,et al.  Estimating the persistence length of a worm-like chain molecule from force-extension measurements. , 1999, Biophysical journal.