Tan Lihua, Schedl Paul, Song Ho-Juhn, Garza Dan, Konsolaki Mary
Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
PLoS One. 2008;3(12):e3966. doi: 10.1371/journal.pone.0003966. Epub 2008 Dec 17.
Alzheimer's (AD) is a progressive neurodegenerative disease that afflicts a significant fraction of older individuals. Although a proteolytic product of the Amyloid precursor protein, the Alphabeta42 polypeptide, has been directly implicated in the disease, the genes and biological pathways that are deployed during the process of Alphabeta42 induced neurodegeneration are not well understood and remain controversial. To identify genes and pathways that mediated Alphabeta42 induced neurodegeneration we took advantage of a Drosophila model for AD disease in which ectopically expressed human Alphabeta42 polypeptide induces cell death and tissue degeneration in the compound eye. One of the genes identified in our genetic screen is Toll (Tl). It encodes the receptor for the highly conserved Tl-->NFkB innate immunity/inflammatory pathway and is a fly homolog of the mammalian Interleukin-1 (Ilk-1) receptor. We found that Tl loss-of-function mutations dominantly suppress the neuropathological effects of the Alphabeta42 polypeptide while gain-of-function mutations that increase receptor activity dominantly enhance them. Furthermore, we present evidence demonstrating that Tl and key downstream components of the innate immunity/inflammatory pathway play a central role in mediating the neuropathological activities of Alphabeta42. We show that the deleterious effects of Alphabeta42 can be suppressed by genetic manipulations of the Tl-->NFkB pathway that downregulate signal transduction. Conversely, manipulations that upregulate signal transduction exacerbate the deleterious effects of Abeta42. Since postmortem studies have shown that the Ilk-1-->NFkB innate immunity pathway is substantially upregulated in the brains of AD patients, the demonstration that the Tl-->NFkB signaling actively promotes the process of Alphabeta42 induced cell death and tissue degeneration in flies points to possible therapeutic targets and strategies.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，困扰着相当一部分老年人。尽管淀粉样前体蛋白的一种蛋白水解产物——αβ42多肽，已被直接认为与该疾病有关，但在αβ42诱导神经退行性变过程中所涉及的基因和生物学途径尚未完全明确，仍存在争议。为了确定介导αβ42诱导神经退行性变的基因和途径，我们利用了一种AD疾病的果蝇模型，其中异位表达的人αβ42多肽会诱导复眼中的细胞死亡和组织退化。我们在基因筛选中确定的一个基因是Toll（Tl）。它编码高度保守的Tl→NFkB固有免疫/炎症途径的受体，是哺乳动物白细胞介素-1（Ilk-1）受体的果蝇同源物。我们发现，Tl功能丧失突变可显著抑制αβ42多肽的神经病理效应，而增加受体活性的功能获得突变则会显著增强这些效应。此外，我们提供的证据表明，Tl和固有免疫/炎症途径的关键下游成分在介导αβ42的神经病理活性中起核心作用。我们表明，通过下调信号转导的Tl→NFkB途径的基因操作，可以抑制αβ42的有害作用。相反，上调信号转导的操作会加剧Aβ42的有害作用。由于死后研究表明，AD患者大脑中Ilk-1→NFkB固有免疫途径显著上调，因此，Tl→NFkB信号在果蝇中积极促进αβ42诱导的细胞死亡和组织退化过程的证明，指出了可能的治疗靶点和策略。
