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oai:repisalud.isciii.es:20.500.12105/179152024-02-10T20:04:02Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927

00925njm 22002777a 4500 dc Martini, Alessandra Cadete author Gomez-Arboledas, Angela author Forner, Stefania author Rodriguez-Ortiz, Carlos J author McQuade, Amanda author Danhash, Emma author Phan, Jimmy author Javonillo, Dominic author Ha, Jordan-Vu author Tram, Melanie author Trujillo-Estrada, Laura author da Cunha, Celia author Ager, Rahasson R author Davila, Jose C author Kitazawa, Masashi author Blurton-Jones, Mathew author Gutierrez, Antonia author Baglietto-Vargas, David author Medeiros, Rodrigo author LaFerla, Frank M author 2019-09-30 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. 10.1073/pnas.1914088116 1091-6490 Proceedings of the National Academy of Sciences of the United States of America http://hdl.handle.net/10668/14569 31570577 http://hdl.handle.net/20.500.12105/17915 3xTg-AD Alzheimer’s disease IL-1R1 TOM1 Target of Myb1 Amyloid-beta impairs TOM1-mediated IL-1R1 signaling.