TY - JOUR
T1 - An improved screening model to identify inhibitors targeting zinc-enhanced amyloid aggregation
AU - Chang, Pei Teh
AU - Kung, Fan Lu
AU - Talekar, Rahul Subhash
AU - Chen, Chien Shu
AU - Lai, Shin Yu
AU - Lee, Hsueh Yun
AU - Chern, Ji Wang
PY - 2009/8/15
Y1 - 2009/8/15
N2 - Zinc, which is abundant in senile plaques consisting mainly of fibrillar β-amyloid (Aβ), plays a critical role in the pathogenesis of Alzheimer's disease. Treatment with zinc chelators such as clioquinol has been used to prevent Aβ aggregation in Alzheimer's patients; however, clioquinol produces severe side effects. A simple, easy, inexpensive, and versatile screen to identify zinc chelators for inhibition of Aβ aggregation is currently unavailable. We thus developed a high-throughput screen that identi-fies zinc chelators with anti-Aβ aggregation activity. The recombinant Aβ peptides, aggregated on solid-phase microplates, formed Aβ-immunopositive β-sheet-containing structures in the presence of zinc. Formation of these Aβ fibrils was specifically blocked by metal ion chelators. This screening model improves identification of zinc-enhanced Aβ fibrils and anti-Aβ aggregation mediated by zinc chelating. The convenient system could qualitatively and quantitatively assay a large sample pool for Aβ aggregation inhibition and dissolution of Aβ aggregates. This screen is practical, reliable, and versatile for comprehensive detection of amyloid fibrillation and identification of inhibitors of Aβ aggregation.
AB - Zinc, which is abundant in senile plaques consisting mainly of fibrillar β-amyloid (Aβ), plays a critical role in the pathogenesis of Alzheimer's disease. Treatment with zinc chelators such as clioquinol has been used to prevent Aβ aggregation in Alzheimer's patients; however, clioquinol produces severe side effects. A simple, easy, inexpensive, and versatile screen to identify zinc chelators for inhibition of Aβ aggregation is currently unavailable. We thus developed a high-throughput screen that identi-fies zinc chelators with anti-Aβ aggregation activity. The recombinant Aβ peptides, aggregated on solid-phase microplates, formed Aβ-immunopositive β-sheet-containing structures in the presence of zinc. Formation of these Aβ fibrils was specifically blocked by metal ion chelators. This screening model improves identification of zinc-enhanced Aβ fibrils and anti-Aβ aggregation mediated by zinc chelating. The convenient system could qualitatively and quantitatively assay a large sample pool for Aβ aggregation inhibition and dissolution of Aβ aggregates. This screen is practical, reliable, and versatile for comprehensive detection of amyloid fibrillation and identification of inhibitors of Aβ aggregation.
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U2 - 10.1021/ac901011e
DO - 10.1021/ac901011e
M3 - Article
C2 - 19621898
AN - SCOPUS:68849121244
SN - 0003-2700
VL - 81
SP - 6944
EP - 6951
JO - Analytical Chemistry
JF - Analytical Chemistry
IS - 16
ER -