Expression in Drosophila of Tandem Amyloid Peptides Provides Insights into Links between Aggregation and

The generation and subsequent aggregation of amyloid (A) peptides play a crucial initiating role in the pathogenesis of Alzheimer disease (AD). The two main isoforms of these pep- tides have 40 (A40) or 42 residues (A42), the latter having a higher propensity to aggregate in vitro and being the main com- ponent of the plaques observed in vivo in AD patients. We have designed a series of tandem dimeric constructs of these A pep- tides to probe the manner in which changes in the aggregation kinetics of A affect its deposition and toxicity in a Drosophila melanogaster model system. The levels of insoluble aggregates were found to be substantially elevated in flies expressing the tandem constructs of both A40 and A42 compared with the equivalent monomeric peptides, consistent with the higher effective concentration, and hence increased aggregation rate, of the peptides in the tandem repeat. A unique feature of the A42 constructs, however, is the appearance of high levels of soluble olig- omeric aggregates and a corresponding dramatic increase in their in vivo toxicity. The toxic nature of the A42 peptide in vivo can therefore be attributed to the higher kinetic stability of the oligo- meric intermediate states that it populates relative to those of A40 rather than simply to its higher rate of aggregation.