Amyloid-beta impairs TOM1-mediated IL-1R1 signaling.
3xTg-AD
Alzheimer’s disease
IL-1R1
TOM1
target of Myb1
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
15 10 2019
15 10 2019
Historique:
pubmed:
2
10
2019
medline:
2
10
2019
entrez:
2
10
2019
Statut:
ppublish
Résumé
Defects in interleukin-1β (IL-1β)-mediated cellular responses contribute to Alzheimer's disease (AD). To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1β inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1β receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic. These data show that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.
Identifiants
pubmed: 31570577
pii: 1914088116
doi: 10.1073/pnas.1914088116
pmc: PMC6800331
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
21198-21206Subventions
Organisme : NIA NIH HHS
ID : P01 AG000538
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG016573
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS082174
Pays : United States
Commentaires et corrections
Type : ErratumIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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