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 tha...

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Autores principales:	Lihua Tan, Paul Schedl, Ho-Juhn Song, Dan Garza, Mary Konsolaki
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c2c1b4b76dca466c8758296a7f9382cd
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spelling	oai:doaj.org-article:c2c1b4b76dca466c8758296a7f9382cd2021-11-25T06:18:10ZThe Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer's Abeta42 polypeptide in Drosophila.1932-620310.1371/journal.pone.0003966https://doaj.org/article/c2c1b4b76dca466c8758296a7f9382cd2008-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19088848/?tool=EBIhttps://doaj.org/toc/1932-6203Alzheimer'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.Lihua TanPaul SchedlHo-Juhn SongDan GarzaMary KonsolakiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 12, p e3966 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lihua Tan Paul Schedl Ho-Juhn Song Dan Garza Mary Konsolaki The Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer's Abeta42 polypeptide in Drosophila.
description	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.
format	article
author	Lihua Tan Paul Schedl Ho-Juhn Song Dan Garza Mary Konsolaki
author_facet	Lihua Tan Paul Schedl Ho-Juhn Song Dan Garza Mary Konsolaki
author_sort	Lihua Tan
title	The Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer's Abeta42 polypeptide in Drosophila.
title_short	The Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer's Abeta42 polypeptide in Drosophila.
title_full	The Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer's Abeta42 polypeptide in Drosophila.
title_fullStr	The Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer's Abeta42 polypeptide in Drosophila.
title_full_unstemmed	The Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer's Abeta42 polypeptide in Drosophila.
title_sort	toll-->nfkappab signaling pathway mediates the neuropathological effects of the human alzheimer's abeta42 polypeptide in drosophila.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/c2c1b4b76dca466c8758296a7f9382cd
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The Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer's Abeta42 polypeptide in Drosophila.

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