Aβ42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila

Aggregation of the amyloid-beta-42 (A beta 42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Ab aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Ab can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of A beta 42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human A beta 42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related (Arc) under bar tic mutation (A beta 42 (arc) under bar) and an (art) under bar ificial mutation (A beta 42 (art) under bar) that is known to suppress aggregation and toxicity of A beta 42 in vitro. In the Drosophila brain, A beta 42Arc formed more oligomers and deposits than did wild type A beta 42, while A beta 42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Ab peptides. Surprisingly, however, A beta 42art caused earlier onset of memory defects than A beta 42. More remarkably, each Ab induced qualitatively different pathologies. A beta 42Arc caused greater neuron loss than did A beta 42, while A beta 42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin S-stained Ab aggregates: A beta 42Arc formed large deposits in the cell body, A beta 42art accumulated preferentially in the neurites, while A beta 42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of A beta 42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo.