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

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which is the most common cause of dementia. Growing evidence exists that instead of amyloid β-protein (Aβ) monomers or fibrils, small and diffusible Aβ oligomers seem to be decisive for disease development and progression1. Thus, the potency to eliminate Aβ oligomers is one of the most desirable criteria for the selection of agents as lead compounds for drug development towards AD treatment2. Any screening for oligomer eliminating compounds requires a well characterized target. Therefore, new methods for the preparation, purification and quantification of specific Aβ oligomers, which are representative for the toxic oligomers involved in AD pathogenesis, are urgently needed in AD drug development. Quantitative assessment of Aβ assembly size-distributions is difficult, because the heterogeneity of in vitro obtained Aβ assemblies3 impedes most of the standard analytical methods. We have designed an assay for the quantitative determination of interference with Aβ aggregate size distribution (QIAD). The QIAD assay, based on a combination of density gradient ultracentrifugation (DGC) and reversed phase high performance liquid chromatography (RP-HPLC), permits the quantitative analysis of the impact of any compound on Aβ aggregation. We applied QIAD on several compounds, i.e., homotaurine, scyllo-inositol, EGCG, the benzofuran derivative {"type":"entrez-protein","attrs":{"text":"KMS88009","term_id":"870800947","term_text":"KMS88009"}}KMS88009, ZAβ3W, the D-enantiomeric peptide D3, and its tandem version D3D3. Comparison of QIAD data obtained for D3 and D3D3 with the treatment effects in AD animal models demonstrates the predictive power of the assay for in vivo efficacy.