OPEN Proceedings of the National Academy of Sciences of the United States of America | 2 Oct 2019
A Cadete Martini, A Gomez-Arboledas, S Forner, CJ Rodriguez-Ortiz, A McQuade, E Danhash, J Phan, D Javonillo, JV Ha, M Tram, L Trujillo-Estrada, C da Cunha, RR Ager, JC Davila, M Kitazawa, M Blurton-Jones, A Gutierrez, D Baglietto-Vargas, R Medeiros and FM LaFerla
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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