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Basic Science and Pathogenesis.

Kevin P Kotredes1, Ravi S Pandey1, Michael Sasner1

  • 1The Jackson Laboratory, Bar Harbor, ME, USA.

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Researchers developed novel mouse models for late-onset Alzheimer's disease (LOAD) to study the IL1RAP gene's role. These models show promise for understanding disease mechanisms and developing new Alzheimer's disease therapeutics.

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Area of Science:

  • Neuroscience
  • Genetics
  • Immunology

Background:

  • Late-onset Alzheimer's disease (LOAD) affects millions, with limited therapeutic options.
  • The IL1RAP gene is a significant risk factor for amyloid accumulation in LOAD.
  • IL1RAP, an IL-1ß receptor, relays immune signals in the central nervous system (CNS).

Purpose of the Study:

  • To investigate the impact of IL1RAP on LOAD pathogenesis.
  • To develop improved preclinical models for LOAD research.

Main Methods:

  • Created two novel mouse strains: a whole-body Il1rap knockout and a neuron-specific Il1rapb conditional knockout.
  • Utilized mouse models with human-relevant genetic backgrounds (APOEε4, Trem2*R47H, humanized App).
  • Administered sterile-infection and high-fat diet insults to exacerbate disease phenotypes.

Main Results:

  • Generated mouse strains exhibiting gene expression signatures similar to human LOAD patients.
  • Observed increased peripheral biomarker neurofilament light chain (NfL), indicating neuronal injury.
  • Confirmed normal immune responses to insults, with elevated inflammatory markers.

Conclusions:

  • Introduced two novel mouse models for studying LOAD with human-relevant genetic backgrounds.
  • These models facilitate the investigation of IL1RAP function in Alzheimer's disease.
  • IL1RAP is a potential therapeutic target for neurodegenerative diseases.