Inhibitors of amyloid β-protein aggregation mediated by GM1-containing raft-like membranes

The aggregation (fibril formation) of amyloid beta-protein (A beta) is considered to be a crucial step in the etiology of Alzheimer's disease (AD). The inhibition of A beta aggregation and/or decomposition of fibrils formed in aqueous solution by small compounds have been studied extensively for the prevention and treatment of AD. However, recent studies suggest that A beta aggregation also occurs in lipid rafts mediated by a cluster of monosialoganglioside GM1. This study examined the effects of representative compounds on At aggregation and fibril destabilization in the presence of GM1-containing raft-like liposomes. Among the compounds tested, nordihydroguaiaretic acid (NDGA), rifampicin (RIF), tannic acid (TA), and quercetin (QUE) showed strong fibrillization inhibitory activity. NDGA and RIF inhibited the binding of A beta to GM1 liposomes by competitively binding to the membranes and/or direct interaction with A beta in solution, thus at least partly preventing fibrils from forming. Coincubation of A beta with NDGA, RIF, and QUE in the presence of GM1 liposomes resulted in elongate particles, whereas the presence of TA yielded protofibrillar structures. TA and RIF also destabilized fibrils. The most potent NDGA prevented A beta-induced toxicity in PC12 cells by inhibiting A beta accumulation. Furthermore, a comparison of the inhibitory effects of various compounds between aqueous-phase and GM1-mediated aggregation of A beta suggested that the two aggregation processes are not identical. (c) 2006 Elsevier B.V. All rights reserved.