An improved screening model to identify inhibitors targeting zinc-enhanced amyloid aggregation.
Zinc, which is abundant in senile plaques consisting mainly of fibrillar beta-amyloid (Abeta), plays a critical role in the pathogenesis of Alzheimer's disease. Treatment with zinc chelators such as clioquinol has been used to prevent Abeta 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 Abeta aggregation is currently unavailable. We thus developed a high-throughput screen that identifies zinc chelators with anti-Abeta aggregation activity. The recombinant Abeta peptides, aggregated on solid-phase microplates, formed Abeta-immunopositive beta-sheet-containing structures in the presence of zinc. Formation of these Abeta fibrils was specifically blocked by metal ion chelators. This screening model improves identification of zinc-enhanced Abeta fibrils and anti-Abeta aggregation mediated by zinc chelating. The convenient system could qualitatively and quantitatively assay a large sample pool for Abeta aggregation inhibition and dissolution of Abeta aggregates. This screen is practical, reliable, and versatile for comprehensive detection of amyloid fibrillation and identification of inhibitors of Abeta aggregation.
Chang
Pei-Teh
PT
School of Pharmacy, National Taiwan University, No. 1, Section 1, Ren-Ai Road, Taipei, 100, Taiwan.
Kung
Fan-Lu
FL
Talekar
Rahul Subhash
RS
Chen
Chien-Shu
CS
Lai
Shin-Yu
SY
Lee
Hsueh-Yun
HY
Chern
Ji-Wang
JW
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology*; D006801:Humans; D008962:Models, Theoretical; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D015032:Zinc