Aβ42 mutants with different aggregation profiles induce distinct pathologies in Drosophila

Koichi Iijima, Hsueh Cheng Chiang, Stephen A. Hearn, Inessa Hakker, Anthony Gatt, Christopher Shenton, Linda Granger, Amy Leung, Kanae Iijima-Ando, Yi Zhong

研究成果: Article同行評審

136 引文 斯高帕斯(Scopus)


Aggregation of the amyloid-β-42 (Aβ42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Aβ aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Aβ can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Aβ42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Aβ42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Aβ42Arc) and an artificial mutation (Aβ42art) that is known to suppress aggregation and toxicity of Aβ42 in vitro. In the Drosophila braih, Aβ42Arc formed more oligomers and deposits than did wild type Aβ42, while Aβ42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Aβ peptides. Surprisingly, however, Aβ42art caused earlier onset of memory defects than Aβ42. More remarkadly, each Aβ induced qualitatively different pathologies. Aβ42Arc caused greater neuron loss than did Aβ42 while Aβ42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin 5-stained Aβ aggregates: Aβ42Arc formed large deposits in the cell body, Aβ42art accumulated preferentially in the neurites, while Aβ42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of Aβ42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo.

期刊PloS one
出版狀態Published - 2008 2月 27

All Science Journal Classification (ASJC) codes

  • 一般生物化學,遺傳學和分子生物學
  • 一般農業與生物科學
  • 多學科


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