Poly-l-lysine Dissolves Fibrillar Aggregation of the Alzheimer β-Amyloid Peptide in Vitro

Nguyen, Khue Vu; Gendrault, Jean-Louis; Wolff, Charles‐Michel

doi:10.1006/bbrc.2002.6514

Cited by 22 publications

(15 citation statements)

References 15 publications

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“…This allows the peptide to interact electrostatically with the coated mica substrate, for an attachment that is strong enough to survive the subsequent washing procedure, with no defined background topography, as reported elsewhere19. It is important to note that when high concentrations of PLL are mixed with Aβ in solution, fibre morphology is disrupted28. However, our technique differs as the protein does not come into contact with the fibres in solution, because the PLL is baked on to the surface of the mica.…”

Section: Resultsmentioning

confidence: 93%

Ultrasonic force microscopy for nanomechanical characterization of early and late-stage amyloid-β peptide aggregation

Tinker-Mill

Mayes

Kolosov

2014

Sci Rep

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The aggregation of amyloid-β peptides into protein fibres is one of the main neuropathological features of Alzheimer's disease (AD). While imaging of amyloid-β aggregate morphology in vitro is extremely important for understanding AD pathology and in the development of aggregation inhibitors, unfortunately, potentially highly toxic, early aggregates are difficult to observe by current electron microscopy and atomic force microscopy (AFM) methods, due to low contrast and variability of peptide attachment to the substrate. Here, we use a poly-L-Lysine (PLL) surface that captures all protein components from monomers to fully formed fibres, followed by nanomechanical mapping via ultrasonic force microscopy (UFM), which marries high spatial resolution and nanomechanical contrast with the non-destructive nature of tapping mode AFM. For the main putative AD pathogenic component, Aβ1-42, the PLL-UFM approach reveals the morphology of oligomers, protofibrils and mature fibres, and finds that a fraction of small oligomers is still present at later stages of fibril assembly.

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Section: Resultsmentioning

confidence: 93%

Ultrasonic force microscopy for nanomechanical characterization of early and late-stage amyloid-β peptide aggregation

Tinker-Mill

Mayes

Kolosov

2014

Sci Rep

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“…A significant fibril-dissolving effect against Ab25-35 was shown (and said to be seen also for Ab1-40 and Ab1-42) and a mechanism was suggested by which poly(L-lysine) binds to Ab25-35 monomers, which are presumed to be present in equilibrium with the fibrils, thereby blocking the monomer-to-fibril reaction. [38] The time needed to obtain dissolution of fibrils was not given but was said to be instantaneous.…”

Section: Dendrimers and Fibrillar Aggregates Of Alzheimer's Disease-rmentioning

confidence: 99%

Dendrimer Effects on Peptide and Protein Fibrillation

Heegaard

Boas

Otzen

2007

Macromolecular Bioscience

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Dendrimers are synthetic, symmetrically branched polymers that can be manufactured to a high degree of definition and therefore present themselves as monodisperse entities. Flexible and globular in shape and compartementalized into a partly inaccessible interior and a highly exposed surface, they offer numerous possibilities for interactions with and responses to biological macromolecules and biostructures including cell membranes and proteins. By way of their multiple functional surface groups, they allow the design of surfaces carrying a multitude of biological motifs and/or charges giving rise to quite significant biological and physico-chemical effects. Here we describe the surprising ability of dendrimers to interact with and perturb polypeptide conformations, particularly efficiently towards amyloid structures; that is, the structures of highly insoluble polypeptide aggregates involved in a range of serious and irreversibly progressive pathological conditions (protein-misfolding diseases). Interesting as this may be, the interaction of dendrimers with such generic peptidic aggregates also offers a new perspective on the molecular mechanisms governing assembly and disassembly of amyloid structures and thereby on determinants of protein and peptide folding. Despite the potent disaggregative nature of various dendrimers, they have variable effects on the stability of different proteins, suggesting that they do not act as generic denaturants, but rather exert their effects via specific interactions with individual parts of each protein.

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“…Interestingly, polylysine is also known to dissolve fibrillar aggregates of Alzheimer's disease amyloid ␤ peptide (A␤; ref. 16).…”

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confidence: 99%

Mechanistic insights into cellular alteration of prion by poly‐D‐lysine: the role of H2H3 domain

Xu¹,

Adrover

Pastore

et al. 2011

FASEB j.

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Misfolding of the prion protein (PrP) is the central feature of prion diseases. The conversion of the normal α-helical PrP(C) into a pathological β-enriched PrP(Sc) constitutes an early event in the infectious process. Several hypotheses, involving different regions of the protein, endeavor to delineate the structural mechanism underlying this change of conformation. All current working hypotheses, however, are based on biophysical and modeling studies, the biological relevance of which still needs to be assessed. We have studied the effect of positively charged polymers on the conversion, using polylysine as a model system, and have investigated a possible mechanism of structural stabilization. We have shown that poly-D-lysine removes proteinase K-resistant PrP from prion-infected SN56 neuroblastoma cells without affecting PrP(C). The effect is enantiospecific since the levorotary isomer, poly-L-lysine, has a markedly weaker effect, likely because of its higher susceptibility to degradation. In vitro cross-linking and NMR studies confirm a direct interaction between polylysine and PrP, which mainly maps to the PrP region containing helices 2 and 3 (H2H3). Interaction prevents conformational conversion and protein aggregation. Our results establish a central role of H2H3 in PrP(Sc) amyloidogenesis and replication and provide biological relevance for the pathological misfolding of this domain.

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Poly-l-lysine Dissolves Fibrillar Aggregation of the Alzheimer β-Amyloid Peptide in Vitro

Cited by 22 publications

References 15 publications

Ultrasonic force microscopy for nanomechanical characterization of early and late-stage amyloid-β peptide aggregation

Ultrasonic force microscopy for nanomechanical characterization of early and late-stage amyloid-β peptide aggregation

Dendrimer Effects on Peptide and Protein Fibrillation

Mechanistic insights into cellular alteration of prion by poly‐D‐lysine: the role of H2H3 domain

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