In:
eLife, eLife Sciences Publications, Ltd, Vol. 2 ( 2013-07-16)
Abstract:
Alzheimer’s disease is the most common form of dementia, estimated to affect roughly five million people in the United States, and its incidence is steadily increasing as the population ages. A pathological hallmark of Alzheimer’s disease is the presence in the brain of aggregates of two proteins: tangles of a protein called tau; and fibers and smaller units (oligomers) of a peptide called amyloid beta. Many attempts have been made to screen libraries of natural and synthetic compounds to identify substances that might prevent the aggregation and toxicity of amyloid. Such studies revealed that polyphenols found in green tea and in the spice turmeric can inhibit the formation of amyloid fibrils. Moreover, a number of dyes reduce the toxic effects of amyloid on cells, although significant side effects prevent these from being used as drugs. Structure-based drug design, in which the structure of a target protein is used to help identify compounds that will interact with it, has been used to generate therapeutic agents for a number of diseases. Here, Jiang et al. report the first application of this technique in the hunt for compounds that inhibit the cytotoxicity of amyloid beta. Using the known atomic structure of the protein in complex with a dye, Jiang et al. performed a computational screen of 18,000 compounds in search of those that are likely to bind effectively. The compounds that showed the strongest predicted binding were then tested for their ability to interfere with the aggregation of amyloid beta and to protect cells grown in culture from its toxic effects. Compounds that reduced toxicity did not reduce the abundance of protein aggregates, but they appear to increase the stability of fibrils. This is consistent with other evidence suggesting that small, soluble forms (oligomers) of amyloid beta that break free from the fibrils may be the toxic agent in Alzheimer’s disease, rather than the fibrils themselves. In addition to uncovering compounds with therapeutic potential in Alzheimer’s disease, this work presents a new approach for identifying proteins that bind to amyloid fibrils. Given that amyloid accumulation is a feature of many other diseases, including Parkinson’s disease, Huntington’s disease and type 2 diabetes, the approach could have broad therapeutic applications.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.00857.001
DOI:
10.7554/eLife.00857.002
DOI:
10.7554/eLife.00857.003
DOI:
10.7554/eLife.00857.004
DOI:
10.7554/eLife.00857.005
DOI:
10.7554/eLife.00857.006
DOI:
10.7554/eLife.00857.007
DOI:
10.7554/eLife.00857.008
DOI:
10.7554/eLife.00857.009
DOI:
10.7554/eLife.00857.010
DOI:
10.7554/eLife.00857.011
DOI:
10.7554/eLife.00857.012
DOI:
10.7554/eLife.00857.013
DOI:
10.7554/eLife.00857.014
DOI:
10.7554/eLife.00857.015
DOI:
10.7554/eLife.00857.016
DOI:
10.7554/eLife.00857.017
DOI:
10.7554/eLife.00857.018
DOI:
10.7554/eLife.00857.019
DOI:
10.7554/eLife.00857.020
DOI:
10.7554/eLife.00857.021
DOI:
10.7554/eLife.00857.022
DOI:
10.7554/eLife.00857.023
DOI:
10.7554/eLife.00857.024
DOI:
10.7554/eLife.00857.025
DOI:
10.7554/eLife.00857.026
DOI:
10.7554/eLife.00857.027
DOI:
10.7554/eLife.00857.028
DOI:
10.7554/eLife.00857.029
DOI:
10.7554/eLife.00857.030
DOI:
10.7554/eLife.00857.031
DOI:
10.7554/eLife.00857.032
DOI:
10.7554/eLife.00857.033
DOI:
10.7554/eLife.00857.034
DOI:
10.7554/eLife.00857.035
DOI:
10.7554/eLife.00857.036
DOI:
10.7554/eLife.00857.037
DOI:
10.7554/eLife.00857.038
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2013
detail.hit.zdb_id:
2687154-3
Permalink