title: Aβ43 is neurotoxic and primes aggregation of Aβ40 in vivo.
abstract: 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.
authors: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931, Cologne, Germany.
authors: Sylvie
authors: S
authors: Burnouf
authors: Marianna Karina
authors: MK
authors: Gorsky
authors: Jacqueline
authors: J
authors: Dols
authors: Sebastian
authors: S
authors: Grönke
authors: Linda
authors: L
authors: Partridge
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila; D005260:Female; D006257:Head / Q000473:pathology / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D017956:Photoreceptor Cells, Invertebrate / Q000473:pathology / Q000502:physiology; D066329:Protein Aggregates; D012333:RNA, Messenger / Q000378:metabolism; D012995:Solubility; D016019:Survival Analysis
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C098994:amyloid beta-protein (1-43)