Basic Science and Pathogenesis

It is estimated that by 2050 the number of Alzheimer's disease (AD) patients will exceed 12 million, 95% of which are sporadic, late-onset AD (LOAD). Without novel therapeutics, unlike other age-related disorders, LOAD mortality will continue to increase. But as next-generation-sequencing technologies improve, human disease risk factors are emerging, correlated to the prevalence and severity of disease. Alterations in the IL1RAP gene are found to be a strong risk factor for amyloid accumulation in LOAD patients. IL1RAP is a membrane-bound IL-1ß receptor expressed in most tissues, including CNS-specific astrocytes, microglia, and neurons, relaying immune signals via NF-κB and MAPK transcription factors. Further, a neuron-specific isoform, IL1RAPb, has been identified and found to disrupt MYD88 scaffolding. As a suspected regulatory mechanism for IL-1ß vulnerability, IL1RAP may prove to be a potential target for intervention against AD.

Mouse models of LOAD are underutilized and in short supply. Most popular AD strains express amyloid-related, familial AD transgenes and fail to address the heterogeneous disregulation observed in human disease. For better preclinical models of LOAD, MODEL-AD has developed novel mouse strains incorporating genetic and environmental risk factors identified from human data sets. To investigate how IL1RAP specifically impacts disease, we have designed two strains expressing loss-of function Il1rap transcripts- a whole body Il1rap knockout and a neuron-specific Il1rapb conditional knockout.

We generated mouse strains on a LOAD-relevant genetic background (APOEε4, Trem2*R47H, and humanized App) and knocked-out Il1rap or I1rapb transcripts which produced gene expression signatures in the brain more similar to those seen in human AD patients. To exacerbate this phenotype, we utilized sterile-infection and high-fat diet insults which produced normal immune responses evidenced by increases in plasma TNFα, IL-6, and IL1RAP agonist, IL-1ß. Both strains also showed an increase in peripheral biomarker neurofilament light chain (NfL), suggesting downstream neuronal injury. More detailed, CNS-specific characterization of the many aspects of IL1RAP function are still in progress.

Here we present two novel mouse strains of LOAD, expressing human-relevant genetic backgrounds aimed at investigating IL1RAP function as a model of human disease and potential target for therapeutic intervention against neurodegeneration.