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

Significance As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses, and the chronic inflammation mediated by inflammatory receptors represents a key mechanism by which amyloid-beta (Aβ) drives the development of cognitive decline in Alzheimer’s disease (AD). A crucial aspect of this process is a failure to resolve inflammation, which involves the suppression of inflammatory cell influx and the endocytosis of inflammatory receptors. We found that ablation of the endosomal adaptor target of Myb1 (TOM1) worsens neuroinflammation, impairs microglial phagocytosis, and significantly exacerbates amyloid deposition. Conversely, restoration of TOM1 reverses these effects and reduces Aβ pathology. These results highlight the importance of endosomal adaptors and their interaction with inflammatory receptors in the pathogenesis of AD.