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Amyloid-beta impairs TOM1-mediated IL-1R1 signaling.

ABSTRACT: Defects in interleukin-1? (IL-1?)-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-1? inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1? 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.

SUBMITTER: Martini AC

PROVIDER: S-EPMC6800331 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Amyloid-beta impairs TOM1-mediated IL-1R1 signaling.

Martini Alessandra Cadete AC Gomez-Arboledas Angela A Forner Stefania S Rodriguez-Ortiz Carlos J CJ McQuade Amanda A Danhash Emma E Phan Jimmy J Javonillo Dominic D Ha Jordan-Vu JV Tram Melanie M Trujillo-Estrada Laura L da Cunha Celia C Ager Rahasson R RR Davila Jose C JC Kitazawa Masashi M Blurton-Jones Mathew M Gutierrez Antonia A Baglietto-Vargas David D Medeiros Rodrigo R LaFerla Frank M FM

Proceedings of the National Academy of Sciences of the United States of America 20190930 42

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 m ...[more]

PMID: 31570577

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Project description:BackgroundMicroglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage.MethodsExcitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell death was assessed in wild type, IL-1R1 null mice, and mice expressing IL-1R1 only in astrocytes.ResultsNMDA-induced damage included neuronal cell death, microglial reactivity, upregulation of pro-inflammatory cytokines, and genes associated with IL1β-signaling in different types of retinal neurons and glia. Expression of the IL1β receptor, IL-1R1, was evident in astrocytes, endothelial cells, some Müller glia, and OFF bipolar cells. Ablation of microglia with clodronate liposomes or Csf1r antagonist (PLX5622) resulted in elevated cell death and diminished neuronal survival in excitotoxin-damaged retinas. Exogenous IL1β stimulated the proliferation and reactivity of microglia in the absence of damage, reduced numbers of dying cells in damaged retinas, and increased neuronal survival following an insult. IL1β failed to provide neuroprotection in the IL-1R1-null retina, but IL1β-mediated neuroprotection was rescued when expression of IL-1R1 was restored in astrocytes.ConclusionsWe conclude that reactive microglia provide protection to retinal neurons, since the absence of microglia is detrimental to survival. We propose that, at least in part, the survival-influencing effects of microglia may be mediated by IL1β, IL-1R1, and interactions of microglia and other macroglia.

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Amyloid-beta impairs TOM1-mediated IL-1R1 signaling.

Publications

Amyloid-beta impairs TOM1-mediated IL-1R1 signaling.

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