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      The Clustering of mApoE Anti-Amyloidogenic Peptide on Nanoparticle Surface Does Not Alter Its Performance in Controlling Beta-Amyloid Aggregation

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          Abstract

          The deposition of amyloid-β (Aβ) plaques in the brain is a significant pathological signature of Alzheimer’s disease, correlating with synaptic dysfunction and neurodegeneration. Several compounds, peptides, or drugs have been designed to redirect or stop Aβ aggregation. Among them, the trideca-peptide CWG-LRKLRKRLLR (mApoE), which is derived from the receptor binding sequence of apolipoprotein E, is effectively able to inhibit Aβ aggregation and to promote fibril disaggregation. Taking advantage of Atomic Force Microscopy (AFM) imaging and fluorescence techniques, we investigate if the clustering of mApoE on gold nanoparticles (AuNP) surface may affect its performance in controlling Aβ aggregation/disaggregation processes. The results showed that the ability of free mApoE to destroy preformed Aβ fibrils or to hinder the Aβ aggregation process is preserved after its clustering on AuNP. This allows the possibility to design multifunctional drug delivery systems with clustering of anti-amyloidogenic molecules on any NP surface without affecting their performance in controlling Aβ aggregation processes.

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          Most cited references39

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          Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles.

          Nanoscale objects are typically internalized by cells into membrane-bounded endosomes and fail to access the cytosolic cell machinery. Whereas some biomacromolecules may penetrate or fuse with cell membranes without overt membrane disruption, no synthetic material of comparable size has shown this property yet. Cationic nano-objects pass through cell membranes by generating transient holes, a process associated with cytotoxicity. Studies aimed at generating cell-penetrating nanomaterials have focused on the effect of size, shape and composition. Here, we compare membrane penetration by two nanoparticle 'isomers' with similar composition (same hydrophobic content), one coated with subnanometre striations of alternating anionic and hydrophobic groups, and the other coated with the same moieties but in a random distribution. We show that the former particles penetrate the plasma membrane without bilayer disruption, whereas the latter are mostly trapped in endosomes. Our results offer a paradigm for analysing the fundamental problem of cell-membrane-penetrating bio- and macro-molecules.
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            In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis.

            Extensive research causally links amyloid-beta peptide (A beta) to Alzheimer's disease, although the pathologically relevant A beta conformation remains unclear. A beta spontaneously aggregates into the fibrils that deposit in senile plaques. However, recent in vivo and in vitro reports describe a potent biological activity for oligomeric assemblies of A beta. To consistently prepare in vitro oligomeric and fibrillar forms of A beta 1-42, a detailed knowledge of how solution parameters influence structure is required. This manuscript represents the first study using a single chemically and structurally homogeneous unaggregated starting material to demonstrate that the formation of oligomers, fibrils, and fibrillar aggregates is determined by time, concentration, temperature, pH, ionic strength, and A beta species. We recently reported that oligomers inhibit neuronal viability 10-fold more than fibrils and approximately 40-fold more than unaggregated peptide, with oligomeric A beta 1-42-induced neurotoxicity significant at 10 nm. In addition, we were able to differentiate by structure and neurotoxic activity wild-type A beta1-42 from isoforms containing familial mutations (Dahlgren, K. N., Manelli, A. M., Stine, W. B., Jr., Baker, L. K., Krafft, G. A., and LaDu, M. J. (2002) J. Biol. Chem. 277, 32046-32053). Understanding the biological role of specific A beta conformations may define the link between A beta and Alzheimer's disease, re-focusing therapeutic approaches by identifying the pernicious species of A beta ultimately responsible for the cognitive dysfunction that defines the disease.
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              Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease

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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                05 February 2020
                February 2020
                : 21
                : 3
                : 1066
                Affiliations
                [1 ]School of Medicine and Surgery, NANOMIB Nanomedicine Center, University of Milano-Bicocca, 20854 Vedano al Lambro (MB), Italy; r.corti9@ 123456campus.unimib.it (R.C.); alcox@ 123456tcd.ie (A.C.); valeria.cassina@ 123456unimib.it (V.C.); luca.nardo@ 123456unimib.it (L.N.); domenico.salerno@ 123456unimib.it (D.S.); claudia.marrano@ 123456unimib.it (C.A.M.); natalia.missana@ 123456unimib.it (N.M.); roberta.dalmagro@ 123456unimib.it (R.D.M.); francesca.re1@ 123456unimib.it (F.R.)
                [2 ]Department of Material Science, University of Milano-Bicocca, 20125 Milan, Italy
                [3 ]IFOM−FIRC Institute of Molecular Oncology, IFOM−IEO Campus, 20139 Milan, Italy; patrizia.andreozzi@ 123456unifi.it
                [4 ]Department of Chemistry “Ugo Schiff”, Università degli Studi di Firenze, 50019 Sesto Fiorentino, Italy
                [5 ]Institute of Materials, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland francesco.stellacci@ 123456epfl.ch (F.S.)
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-4737-7900
                https://orcid.org/0000-0001-9484-4922
                https://orcid.org/0000-0002-0254-8243
                https://orcid.org/0000-0001-9602-0935
                https://orcid.org/0000-0003-1374-567X
                https://orcid.org/0000-0003-4257-2165
                Article
                ijms-21-01066
                10.3390/ijms21031066
                7036774
                32033502
                66033e46-cf98-4886-98b2-fd59a1b81aef
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 09 January 2020
                : 03 February 2020
                Categories
                Article

                Molecular biology
                amyloid-β,mapoe,afm,gold nanoparticles
                Molecular biology
                amyloid-β, mapoe, afm, gold nanoparticles

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