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The Molecular Assembly of Amyloid A beta Controls Its Neurotoxicity and Binding to Cellular Proteins

Manzoni, C; Colombo, L; Bigini, P; Diana, V; Cagnotto, A; Messa, M; Lupi, M; ... Salmona, M; + view all (2011) The Molecular Assembly of Amyloid A beta Controls Its Neurotoxicity and Binding to Cellular Proteins. PLOS ONE , 6 (9) , Article e24909. 10.1371/journal.pone.0024909. Green open access

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Abstract

Accumulation of beta-sheet-rich peptide (A beta) is strongly associated with Alzheimer's disease, characterized by reduction in synapse density, structural alterations of dendritic spines, modification of synaptic protein expression, loss of long-term potentiation and neuronal cell death. A beta species are potent neurotoxins, however the molecular mechanism responsible for A beta toxicity is still unknown. Numerous mechanisms of toxicity were proposed, although there is no agreement about their relative importance in disease pathogenesis. Here, the toxicity of A beta 1-40 and A beta 1-42 monomers, oligomers or fibrils, was evaluated using the N2a cell line. A structure-function relationship between peptide aggregation state and toxic properties was established. Moreover, we demonstrated that A beta toxic species cross the plasma membrane, accumulate in cells and bind to a variety of internal proteins, especially on the cytoskeleton and in the endoplasmatic reticulum (ER). Based on these data we suggest that numerous proteins act as A beta receptors in N2a cells, triggering a multi factorial toxicity.

Type: Article
Title: The Molecular Assembly of Amyloid A beta Controls Its Neurotoxicity and Binding to Cellular Proteins
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0024909
Publisher version: http://dx.doi.org/10.1371/journal.pone.0024909
Language: English
Additional information: © 2011 Manzoni et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Banca IntesaSanPaolo and Fondazione Cariplo Proget NOBEL-GUARD provided financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: 2-DIMENSIONAL GEL-ELECTROPHORESIS, INTEGRAL MEMBRANE-PROTEINS, ALZHEIMERS-DISEASE, PRION PROTEIN, ACTIVATION, OLIGOMERS, RECEPTOR, BRAIN, PURIFICATION, RENATURATION
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1327651
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