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Abstract
Insufficiencies of the micronutrient thiamine (Vitamin B1) have been associated with inducing Alzheimer’s Disease (AD)-like neuropathology. Thiamine is a critical enzyme cofactor within the glycolytic metabolic network that is fundamentally required to sustain the bioenergetic and anabolic needs of all cells. The hypometabolic state associated with chronic thiamine insufficiency (TI) has been demonstrated to be a contributor towards the development of amyloid plaque deposition and neurotoxicity within the thalamus, hippocampus, and cortex. However, the molecular mechanism underlying TI induced AD pathology is still unresolved. Previously, we have established that TI stabilizes the metabolic stress transcriptional factor, Hypoxia Inducible Factor-1α (HIF1α). Utilizing neuronal hippocampal cells, TI-induced HIF1α activation triggered the amyloidogenic cascade through transcriptional activation and increased activity of b-secretase (BACE1). Knockdown and pharmacological inhibition of HIF1α significantly reduced BACE1 and C99 formation. TI also increased the expression of the HIF1α regulated pro-apoptotic protein, BNIP3. Correspondingly, cell toxicity during TI conditions was significantly reduced with HIF1α and BNIP3 knockdown.
The role of BNIP3 in TI-mediated toxicity was further highlighted by localization of dimeric BNIP3 into the mitochondria and nuclear accumulation of Endonuclease G. Cell toxicity via the HIF1α/BNIP3 cascade required TI induced oxidative stress. TI decreased mitochondrial membrane potential and enhanced chromatin fragmentation. In addition, we observed that HIF1α, BACE1 and BNIP3 expression was induced in 3xTg AD mice after TI. Treatment with the HIF1α inhibitor YC1 significantly attenuated HIF1α and target genes levels.
Overall, these findings demonstrate a critical stress response during TI involving the induction of HIF1α transcriptional activity that directly promotes neurotoxicity and AD-like pathology.