| First Author | Valle ML | Year | 2022 |
| Journal | Mol Cell Neurosci | Volume | 123 |
| Pages | 103785 | PubMed ID | 36241022 |
| Mgi Jnum | J:348507 | Mgi Id | MGI:7378097 |
| Doi | 10.1016/j.mcn.2022.103785 | Citation | Valle ML, et al. (2022) Thiamine insufficiency induces Hypoxia Inducible Factor-1alpha as an upstream mediator for neurotoxicity and AD-like pathology. Mol Cell Neurosci 123:103785 |
| abstractText | Insufficiencies of the micronutrient thiamine (Vitamin B1) have been associated with inducing Alzheimer's disease (AD)-like neuropathology. 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. 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-1alpha (HIF1alpha). Utilizing neuronal hippocampal cells (HT22), TI-induced HIF1alpha activation triggered the amyloidogenic cascade through transcriptional expression and increased activity of beta-secretase (BACE1). Knockdown and pharmacological inhibition of HIF1alpha during TI significantly reduced BACE1 and C-terminal Fragment of 99 amino acids (C99) formation. TI also increased the expression of the HIF1alpha regulated pro-apoptotic protein, BCL2/adenovirus E1B 19 kDa protein-interacting protein (BNIP3). Correspondingly, cell toxicity during TI conditions was significantly reduced with HIF1alpha 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. Subsequently, TI decreased mitochondrial membrane potential and enhanced chromatin fragmentation. However, cell toxicity via the HIF1alpha/BNIP3 cascade required TI induced oxidative stress. HIF1alpha, BACE1 and BNIP3 expression was induced in 3xTg-AD mice after TI and administration with the HIF1alpha inhibitor YC1 significantly attenuated HIF1alpha and target genes levels in vivo. Overall, these findings demonstrate a critical stress response during TI involving the induction of HIF1alpha transcriptional activity that directly promotes neurotoxicity and AD-like pathology. |
