T-2 Toxin Disrupts Alzheimer's-relevant App/Tau Homeostasis via Circadian-p53-Senescence Crosstalk: Evidence from Human Neuroblastoma Cells.

Abstract

Environmental mycotoxins are pervasive exposures, yet how they perturb Alzheimer's disease (AD)-relevant proteostasis remains unclear. We treated SH-SY5Y cells with low-dose T-2 toxin (6nM) for 24h, and profiled AD-relevant protein changes alongside transcriptomic, circadian, and senescence-related readouts. We report that T‑2 toxin remodels APP and Tau homeostasis, featuring an early decrease in full‑length APP and a delayed, sustained increase in Tau phosphorylation and total Tau, accompanied by dynamic cytokine release. RNA‑seq at 12h revealed a p53‑centered stress response and enrichment of circadian‑related pathways. Cosinor analysis indicated that CLOCK rhythmicity is preserved but reparameterized following T-2 toxin exposure, with a marked phase shift and an elevated mesor. Pharmacological disruption of CLOCK attenuated p53 induction and Tau elevation, whereas inhibition of p53 partially restored APP and reduced Tau changes while reshaping CLOCK abundance and localization, consistent with CLOCK-p53 cross‑regulation. T‑2 toxin also induced a time‑dependent senescence‑like phenotype that was attenuated by CLOCK and/or p53 inhibition. Post‑treatment with senolytic drugs dasatinib and quercetin reduced SA‑β‑gal burden, dampened p53 signaling, and improved the APP/Tau profile. Together, these data link T‑2 toxin exposure to AD‑relevant proteostasis remodeling through a CLOCK-p53-senescence axis and suggest circadian and senescence‑targeting strategies as complementary intervention points.