53
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      QIAD assay for quantitating a compound’s efficacy in elimination of toxic Aβ oligomers

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Strong evidence exists for a central role of amyloid β-protein (Aβ) oligomers in the pathogenesis of Alzheimer’s disease. We have developed a fast, reliable and robust in vitro assay, termed QIAD, to quantify the effect of any compound on the Aβ aggregate size distribution. Applying QIAD, we studied the effect of homotaurine, scyllo-inositol, EGCG, the benzofuran derivative KMS88009, ZAβ3W, the D-enantiomeric peptide D3 and its tandem version D3D3 on Aβ aggregation. The predictive power of the assay for in vivo efficacy is demonstrated by comparing the oligomer elimination efficiency of D3 and D3D3 with their treatment effects in animal models of Alzheimer´s disease.

          Related collections

          Most cited references25

          • Record: found
          • Abstract: found
          • Article: not found

          EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers.

          The accumulation of beta-sheet-rich amyloid fibrils or aggregates is a complex, multistep process that is associated with cellular toxicity in a number of human protein misfolding disorders, including Parkinson's and Alzheimer's diseases. It involves the formation of various transient and intransient, on- and off-pathway aggregate species, whose structure, size and cellular toxicity are largely unclear. Here we demonstrate redirection of amyloid fibril formation through the action of a small molecule, resulting in off-pathway, highly stable oligomers. The polyphenol (-)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both alpha-synuclein and amyloid-beta by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of beta-sheet-rich amyloid, the formation of unstructured, nontoxic alpha-synuclein and amyloid-beta oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?

            Amyloid beta (Abeta) is a small self-aggregating peptide produced at low levels by normal brain metabolism. In Alzheimer's disease (AD), self-aggregation of Abeta becomes rampant, manifested most strikingly as the amyloid fibrils of senile plaques. Because fibrils can kill neurons in culture, it has been argued that fibrils initiate the neurodegenerative cascades of AD. An emerging and different view, however, is that fibrils are not the only toxic form of Abeta, and perhaps not the neurotoxin that is most relevant to AD: small oligomers and protofibrils also have potent neurological activity. Immuno-neutralization of soluble Abeta-derived toxins might be the key to optimizing AD vaccines that are now on the horizon.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              An in vitro model for neuroscience: differentiation of SH-SY5Y cells into cells with morphological and biochemical characteristics of mature neurons.

              Neuroscience, including research on Alzheimer's disease, is hampered by the lack of suitable in vitro models to study the human nervous system. To counteract this, many attempts to differentiate cell lines into more neuron-like cells have been performed, resulting in partial expression of neuronal features. Furthermore, it has been reported that neuroblastoma cell lines lack mature isoforms of tau. Our aim was to develop an improved in vitro model, generating sustainable cells with morphology and biochemistry of human, mature neurons. To obtain cells with neuronal differentiation and function, we investigated the effect of combining three-dimensional culturing of SH-SY5Y cells in extracellular matrix (ECM) gel with several factors reported to have neuro-differentiating effects. This resulted in cells with apparent neuronal morphology with long, extensively branched neurites. Further investigation revealed expression of several neurospecific markers including synapse protein Sv2 and nuclear marker NeuN, as well as the presence of synapses and axonal vesicle transport. In addition, these cells expressed mature tau isoforms, and tau protein expression was significantly increased compared to undifferentiated cells, reaching levels found in adult human brain. In conclusion, we found that pre-treatment with retinoic acid followed by ECM gel culturing in combination with brain derived neurotrophic factor, neuregulin beta1, nerve growth factor, and vitamin D3 treatment generated sustainable cells with unambiguous resemblance to adult neurons. These cells also expresses adult splicing forms of tau with neuronal localization, making this cellular in vitro model useful in many areas of neuroscience research, particularly the Alzheimer's disease field.
                Bookmark

                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                23 September 2015
                2015
                : 5
                : 13222
                Affiliations
                [1 ]Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Centre Jülich , 52425 Jülich, Germany
                [2 ]Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40225 Düsseldorf, Germany
                [3 ]Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham , Birmingham, AL, USA
                [4 ]Institute of Neuroscience and Medicine (INM-4), Research Centre Jülich (FZJ) , 52425 Jülich, Germany
                [5 ]Institute for Bioorganic Chemistry, Heinrich-Heine-Universität Düsseldorf , 52426 Jülich, Germany
                [6 ]Institut für Bio- und Geowissenschaften: Biotechnologie (IBG-1), Forschungszentrum Jülich , 52428 Jülich, Germany
                [7 ]Fraunhofer Institute for Cell Therapy and Immunology, Dep. Molecular Drug Biochemistry and Therapy , 06120 Halle, Germany
                [8 ]Bioanalytik, Hochschule für Angewandte Wissenschaften , Coburg, Germany
                [9 ]Institute of Mathematics, Lehrstuhl für Statistik und Wahrscheinlichkeitstheorie, Heinrich-Heine-Universität Düsseldorf , 40225 Düsseldorf, Germany
                Author notes
                Article
                srep13222
                10.1038/srep13222
                4585794
                26394756
                6e88e9f4-440d-43c5-a9f1-33832232e5bb
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 07 May 2015
                : 21 July 2015
                Categories
                Article

                Uncategorized
                Uncategorized

                Comments

                Comment on this article