Aβ40 Protects Non-toxic Aβ42 Monomer from Aggregation

Abstract

Aβ40 and Aβ42 are the predominant Aβ species in the human body. Toxic Aβ42 oligomers and fibrils are believed to play a key role in causing Alzheimer's disease (AD). However, the role of Aβ40 in AD pathogenesis is not well established. Emerging evidence indicates a protective role for Aβ40 in AD pathogenesis. Although Aβ40 is known to inhibit Aβ42 fibril formation, it is not clear whether the inhibition acts on the non-toxic monomer or acts on the toxic Aβ42 oligomers. In contrast to conventional methods that detect the appearance of fibrils, in our study Aβ42 aggregation was monitored by the decreasing NMR signals from Aβ42 monomers. In addition, differential NMR isotope labelling enabled the selective observation of Aβ42 aggregation in a mixture of Aβ42 and Aβ40. We found Aβ40 monomers inhibit the aggregation of non-toxic Aβ42 monomers, in an Aβ42/Aβ40 ratio-dependent manner. NMR titration revealed that Aβ40 monomers bind to Aβ42 aggregates with higher affinity than Aβ42 monomers. Aβ40 can also release Aβ42 monomers from Aβ42 aggregates. Thus, Aβ40 likely protects Aβ42 monomers by competing for the binding sites on pre-existing Aβ42 aggregates. Combining our data with growing evidence from transgenic mice and human genetics, we propose that Aβ40 plays a critical, protective role in Alzheimer's by inhibiting the aggregation of Aβ42 monomer. Aβ40 itself, a peptide already present in the human body, may therefore be useful for AD prevention and therapy.