NABi, a novel beta-sheet breaker, inhibits A beta aggregation and neuronal toxicity: Therapeutic implications for Alzheimer's disease

Abstract

Amyloid beta (A beta) aggregates are an important therapeutic target for Alzheimer's disease (AD), a fatal neuro-degenerative disease. To date, AD still remains a big challenge due to no effective treatments. Based on the property that A beta aggregates have the cross-beta-structure, a common structural feature in amyloids, we systemically designed the A beta-aggregation inhibitor that maintains A beta-interacting ability but removes toxic part from SOD1 (superoxide dismutase 1)-G93A. We identified NABi (Natural A beta Binder and A beta-aggregation inhibitor) composed of beta 2-3 strands, a novel breaker of A beta aggregation, which does not self-aggregate and has no cytotoxicity at all. The NABi blocks A beta-fibril formation in vitro and in vivo and prevents neuronal cell death, a hallmark of AD pathogenesis. Such anti-amyloidogenic properties can provide novel strategies for treating AD. Furthermore, our study provides molecular insights into the design of amyloidogenic inhibitors to cure various neurodegenerative and amyloid-associated diseases, as NABi would regulate aggregation of other toxic beta-sheet proteins other than A beta.