Global Deficiency of Alzheimer’s Disease Risk Gene Il1rap Reduces Pathological Tau in a Mouse Model of Systemic Inflammation
Year: 2025
Type: article
Abstract: Brain inflammation is strongly associated with neurodegeneration in Alzheimer’s disease (AD) and related tauopathies. We have previously demonstrated that microglia-derived interleukin-1β (IL-1β) induces tau hyperphosphorylation in a cell-autonomous manner and depends on activating the IL-1 receptor (IL-1R1) signaling pathway. IL-1 receptor accessory protein (IL-1RAcP) is a co-receptor for IL-1R1 and is essential for the IL-1R1 receptor function and downstream signaling. Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) in the IL1RAP gene that have been shown to increase AD risk. Here, we demonstrate that global and neuron-specific isoform deficiency of IL-1RAcP regulates hyperphosphorylated tau levels in a lipopolysaccharide (LPS)-induced mouse model of systemic inflammation. Notably, while global Il1rap-/- reduced pS202(AT8) and pT231 (AT180) tau levels, neuron-specific IL-1RAcP (IL-1RAcPb) deficiency specifically increased total tau levels. Together, these results suggest that IL-1RAcP is an important regulator of tau hyperphosphorylation relevant to AD and related tauopathies.
Source: ASN NEURO
Authors: Somayeh Dadras, Kiran Bhaskar
Institution: University of New Mexico
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,950
Funders: Amgen, University of New Mexico, University of Washington, National Institutes of Health, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity
Awards: G1235384288, G1428819660, G1773891675, G2639472435, Validation of a novel tau clearance mechanism., G4224976707, G4982566866, AIM-AHEAD Coordinating Center - All Four Cores, G9000064959, G9000140553, G9000149780, G9000197528, G9000292904, New Mexico Alzheimer's Disease Research Center, Autophagy, Inflammation and Metabolism (AIM) in Disease Center - Phase 2.
OpenAlex ID: W4417088205