The Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer's Abeta42 polypeptide in Drosophila.

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.