The Toll→NFκB Signaling Pathway Mediates the Neuropathological Effects of the Human Alzheimer's Aβ42 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 A beta 42 polypeptide, has been directly implicated in the disease, the genes and biological pathways that are deployed during the process of A beta 42 induced neurodegeneration are not well understood and remain controversial. To identify genes and pathways that mediated A beta 42 induced neurodegeneration we took advantage of a Drosophila model for AD disease in which ectopically expressed human A beta 42 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 -> NF kappa B 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 A beta 42 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 A beta 42. We show that the deleterious effects of A beta 42 can be suppressed by genetic manipulations of the Tl -> NF kappa B pathway that downregulate signal transduction. Conversely, manipulations that upregulate signal transduction exacerbate the deleterious effects of A beta 42. Since postmortem studies have shown that the Ilk-1 -> NF kappa B innate immunity pathway is substantially upregulated in the brains of AD patients, the demonstration that the Tl -> NF kappa B signaling actively promotes the process of A beta 42 induced cell death and tissue degeneration in flies points to possible therapeutic targets and strategies.