Vitamin B1 protects against Aβ1-42-induced HIF-1α activation and neurotoxicity

Abstract

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and extensive neuronal loss, largely driven by amyloid beta (Aβ) accumulation and associated cellular stress. Vitamin B1 (thiamine) supplementation has demonstrated cognitive benefits in clinical AD studies, however, the mechanisms underlying thiamine's neuroprotective effects remain unclear. Here, we investigated whether thiamine mitigates Aβ_1-42-induced neurotoxicity by suppressing hypoxia-inducible factor-1 alpha (HIF-1α), a transcriptional stress factor regulating many proapoptotic and progressive amyloidogenic pathways. Exposure of neuronal cells to Aβ_1-42 oligomers increased reactive oxygen species (ROS) accumulation, decreased intracellular Fe²⁺, and induced HIF-1α stabilization. HIF-1α activation by Aβ_1-42 promoted apoptosis through increased endoplasmic reticulum (ER) stress and increased mitochondrial dimerization of BNIP3. Thiamine supplementation significantly reduced cellular ROS levels, preserved intracellular Fe²⁺ levels, and restored prolyl hydroxylase (PHD) activity to promote HIF-1α hydroxylation and degradation. Suppression of HIF-1α by thiamine attenuated ER and BNIP3-driven apoptotic pathways and preserved neuronal viability. Thiamine further mitigated HIF-1α-mediated amyloidogenic progression, limiting feedback toxicity caused by Aβ_1-42. These results demonstrate that thiamine protects against Aβ_1-42-mediated neurotoxicity by reducing ROS, preserving Fe²⁺, and inhibiting HIF-1α-driven pathological cascades. Overall, this study identified a novel mechanism for thiamine's neuroprotective role, further supporting its therapeutic potential to limit neurodegenerative progression in AD.