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Basic Science and Pathogenesis.

Somayeh Dadras1, Cristian Bologa1, Tione Buranda2

  • 1University of New Mexico, Albuquerque, NM, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
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Summary
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Targeting IL-1 receptor accessory protein (IL-1RAP) reduces neuroinflammation and tau pathology in Alzheimer's disease (AD) models. This suggests IL-1RAP inhibition as a potential therapeutic strategy for AD and other inflammatory conditions.

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Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Alzheimer's disease (AD) and tauopathies are leading causes of death with no cure.
  • Interleukin-1 beta (IL-1β)-induced inflammation significantly contributes to tau pathology, neurodegeneration, and cognitive decline in AD.
  • IL-1 receptor accessory protein (IL-1RAP) is a key co-receptor in IL-1β signaling and is genetically linked to AD risk.

Purpose of the Study:

  • To investigate the role of IL-1RAP in AD and tauopathies.
  • To determine the effects of genetic IL-1RAP depletion on neuroinflammation and tau pathology.
  • To identify pharmaceutical inhibitors of the IL-1R1/IL-1RAP signaling axis.

Main Methods:

  • Generated IL-1RAP myeloid-cell restricted conditional knockout (mcKO) mice crossed with the PS19 tauopathy model.
  • Assessed tau pathology using Western blotting and immunohistochemistry (IHC).
  • Measured inflammatory cytokines via Meso Scale Discovery (MSD) and screened a chemical library for IL-1R1/IL-1RAP inhibitors.

Main Results:

  • IL-1RAP knockout mice showed significantly reduced tau pathology and proinflammatory cytokines.
  • Twenty small molecule drugs were identified as inhibitors of the IL-1R1/IL-1RAP signaling axis.
  • Behavioral tests are ongoing to evaluate cognitive improvements in knockout mice.

Conclusions:

  • Inhibiting the IL-1R1/IL-1RAP signaling pathway effectively reduces neuroinflammation and tau pathology.
  • Targeting IL-1RAP presents a promising therapeutic strategy for Alzheimer's disease.
  • This approach may also benefit other inflammatory diseases.