An Aβ42 variant that inhibits intra- and extracellular amyloid aggregation and enhances cell viability

Aggregation and accumulation of the 42-residue amyloid beta peptide (A beta 42) in the extracellular matrix and within neuronal cells is considered a major cause of neuronal cell cytotoxicity and death in Alzheimer's disease (AD) patients. Therefore, molecules that bind to A beta 42 and prevent its aggregation are therapeutically promising as AD treatment. Here, we show that a non-self-aggregating A beta 42 variant carrying two surface mutations, F19S and L34P (A beta 42(DM)), inhibits wild-type A beta 42 aggregation and significantly reduces A beta 42-mediated cell cytotoxicity. In addition, A beta 42(DM) inhibits the uptake and internalization of extracellularly added pre-formed A beta 42 aggregates into cells. This was the case in both neuronal and non-neuronal cells co-expressing A beta 42 and A beta 42(DM) or following pre-treatment of cells with extracellular soluble forms of the two peptides, even at high A beta 42 to A beta 42(DM) molar ratios. In cells, A beta 42(DM) associates with A beta 42, while in vitro, the two soluble recombinant peptides exhibit nano-molar binding affinity. Importantly, A beta 42(DM) potently suppresses A beta 42 amyloid aggregation in vitro, as demonstrated by thioflavin T fluorescence and transmission electron microscopy for detecting amyloid fibrils. Overall, we present a new approach for inhibiting A beta 42 fibril formation both within and outside cells. Accordingly, A beta 42(DM) should be evaluated in vivo for potential use as a therapeutic lead for treating AD.