Abeta42 mutants with different aggregation profiles induce distinct pathologies in Drosophila.
Abeta42 mutants with different aggregation profiles induce distinct pathologies in Drosophila.
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DOI：
10.1371/journal.pone.0001703
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发表时间：
2008-02-27
期刊：
影响因子：
3.7
通讯作者：
Zhong Y
中科院分区：
文献类型：
--
作者：
Iijima K;Chiang HC;Hearn SA;Hakker I;Gatt A;Shenton C;Granger L;Leung A;Iijima-Ando K;Zhong Y
淀粉样β-42（Aβ42）肽在脑实质中的聚集是阿尔茨海默病（AD）的病理标志，并且已经提出预防Aβ聚集作为AD的治疗干预。然而，最近的报告表明，Aβ可以形成几种不同的前纤维和纤维聚集体，并且每种聚集体可能产生不同的致病作用，这表明操纵Aβ42聚集不仅可以定量，而且可以定性地改变脑病理学。在这里，我们比较了具有不同聚集倾向的人Aβ42突变体的致病性。我们检查了易聚集的EOFAD相关Arctic突变（Aβ 42 Arc）和已知在体外抑制Aβ42聚集和毒性的人工突变（Aβ 42 art）。在果蝇脑中，Aβ 42 Arc比野生型Aβ42形成更多的寡聚体和沉积物，而Aβ 42 art形成更少的寡聚体和沉积物。运动功能障碍和过早死亡的严重程度与Aβ肽的聚集趋势呈正相关。然而，令人惊讶的是，Aβ 42 art比Aβ42更早引起记忆缺陷。更值得注意的是，每种Aβ诱导的病理性质不同。Aβ 42 Arc比Aβ42引起更大的神经元丢失，而Aβ 42 art果蝇表现出最强的神经突变性。这种变性模式与硫磺素S染色的Aβ聚集体的分布一致：Aβ 42 Arc在细胞体中形成大量沉积物，Aβ 42 art优先在神经突中积聚，而Aβ42在两个位置积聚。我们的研究结果表明，操纵Aβ42的聚集倾向不仅会改变毒性水平，而且还可能导致体内诱导的病理学发生质的变化。
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 brain, 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 remarkably, 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 S-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.
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影响因子：
56.9
作者：
Meyer-Luehmann, Melanie;Coomaraswamy, Janaky;Jucker, Mathias
通讯作者：
Jucker, Mathias
影响因子：
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Johansson, Ann-Sofi;Berglind-Dehlin, Fredrik;Lannfelt, Lars
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Lannfelt, Lars
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作者：
Lord, A;Kalimo, H;Nilsson, LNG
通讯作者：
Nilsson, LNG
影响因子：
25
作者：
Nilsberth, C;Westlind-Danielsson, A;Lannfelt, L
通讯作者：
Lannfelt, L
影响因子：
3.9
作者：
GANETZKY, B;FLANAGAN, JR
通讯作者：
FLANAGAN, JR