Aβ₄₃ is neurotoxic and primes aggregation of Aβ₄₀ in vivo

The involvement of Amyloid-β (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is well established. However, it is becoming clear that the amyloid load in AD brains consists of a heterogeneous mixture of Aβ peptides, implying that a thorough understanding of their respective role and toxicity is crucial for the development of efficient treatments. Besides the well-studied Aβ₄₀ and Aβ₄₂ species, recent data have raised the possibility that Aβ₄₃ peptides might be instrumental in AD pathogenesis, because they are frequently observed in both dense and diffuse amyloid plaques from human AD brains and are highly amyloidogenic in vitro. However, whether Aβ₄₃ is toxic in vivo is currently unclear. Using Drosophila transgenic models of amyloid pathology, we show that Aβ₄₃ peptides are mainly insoluble and highly toxic in vivo, leading to the progressive loss of photoreceptor neurons, altered locomotion and decreased lifespan when expressed in the adult fly nervous system. In addition, we demonstrate that Aβ₄₃ species are able to trigger the aggregation of the typically soluble and non-toxic Aβ₄₀, leading to synergistic toxic effects on fly lifespan and climbing ability, further suggesting that Aβ₄₃ peptides could act as a nucleating factor in AD brains. Altogether, our study demonstrates high pathogenicity of Aβ₄₃ species in vivo and supports the idea that Aβ₄₃ contributes to the pathological events leading to neurodegeneration in AD.