Amyloid-beta Impairs TOM1-mediated IL-1R1 Signaling

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2019 Oct 2

PMID 31570577

Citations 11

Authors

Alessandra Cadete Martini

Angela Gomez-Arboledas

Stefania Forner

Carlos J Rodriguez-Ortiz

Amanda McQuade

Emma Danhash

Jimmy Phan

Dominic Javonillo

Jordan-Vu Ha

Melanie Tram

Laura Trujillo-Estrada

Celia Da Cunha

Rahasson R Ager

Jose C Davila

Masashi Kitazawa

Mathew Blurton-Jones

Antonia Gutierrez

David Baglietto-Vargas

Rodrigo Medeiros

Frank M LaFerla

Affiliations

Soon will be listed here.

Abstract

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.

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