IL-1β neutralization ameliorates cognitive deficits and tau pathology in a mouse model of Alzheimer's disease with hyperhomocysteinemia.

Abstract

BACKGROUND: Hyperhomocysteinemia (HHcy) is an important risk factor for Alzheimer's disease (AD), but its differential effects on tau pathology and beta-amyloid (Aβ) deposition, as well as the key mediating molecules involved, remain unclear. This study investigates how HHcy influences AD pathology and examines whether interleukin-1β (IL-1β) neutralization can mitigate HHcy-accelerated neurodegeneration. METHODS: Female 12-month-old 3 × Tg-AD mice were supplemented with methionine water for 7 weeks to induce HHcy. Brain tissues were analyzed for Aβ deposition, tau phosphorylation, oligomerization, and neurofibrillary tangle formation using ELISA, immunohistochemistry, Western blot, and Thioflavin S staining. To assess the role of IL-1β, HHcy-AD mice were treated with an anti-IL-1β monoclonal antibody (mAb; 100 μg, twice weekly for two weeks). Moreover, behavioral performance was evaluated using the Morris water maze for the effect of IL-1β neutralization. RESULTS: HHcy significantly exacerbated tau pathology, increasing oligomeric tau levels, hyperphosphorylation (AT-8, Ser396, Thr231), and neurofibrillary tangles, particularly in the cortex. In contrast, HHcy had minimal effects on Aβ deposition, only increasing insoluble Aβ1-40. Anti-IL-1β mAb treatment reduced tau phosphorylation and oligomerization, coinciding with inactivation of hippocampal GSK3β (increased p-Ser9). The mAb also improved cognitive function but showed selective effects on Aβ pathology and differentially modulated glial responses across brain regions. CONCLUSION: HHcy preferentially exacerbates tauopathy rather than amyloidosis in 3 × Tg-AD mice. IL-1β neutralization ameliorates tau-related pathology and cognitive deficits, likely through regional suppression of GSK3β activity, highlighting its potential as a therapeutic strategy for tau-focused AD interventions.