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Abeta is neurotoxic and primes aggregation of Abeta in vivo

MPG-Autoren

Burnouf,  S.
Max Planck Institute for Biology of Ageing, Max Planck Society;

Gorsky,  M. K.
Max Planck Institute for Biology of Ageing, Max Planck Society;

Dols,  J.
Max Planck Institute for Biology of Ageing, Max Planck Society;

Gronke,  S.
Max Planck Institute for Biology of Ageing, Max Planck Society;

Partridge,  L.
Max Planck Institute for Biology of Ageing, Max Planck Society;

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Zitation

Burnouf, S., Gorsky, M. K., Dols, J., Gronke, S., & Partridge, L. (2015). Abeta is neurotoxic and primes aggregation of Abeta in vivo. Acta Neuropathol. doi:10.1007/s00401-015-1419-y.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0028-58AC-B
Zusammenfassung
The involvement of Amyloid-beta (Abeta) 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 Abeta peptides, implying that a thorough understanding of their respective role and toxicity is crucial for the development of efficient treatments. Besides the well-studied Abeta40 and Abeta42 species, recent data have raised the possibility that Abeta43 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 Abeta43 is toxic in vivo is currently unclear. Using Drosophila transgenic models of amyloid pathology, we show that Abeta43 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 Abeta43 species are able to trigger the aggregation of the typically soluble and non-toxic Abeta40, leading to synergistic toxic effects on fly lifespan and climbing ability, further suggesting that Abeta43 peptides could act as a nucleating factor in AD brains. Altogether, our study demonstrates high pathogenicity of Abeta43 species in vivo and supports the idea that Abeta43 contributes to the pathological events leading to neurodegeneration in AD.