Implications of Metabolic Dysfunction during Thiamine Insufficiency

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Project Summary Declining vitamin B1 (thiamine) blood levels significantly correlates with a deterioration in cognitive function and is associated with promoting Alzheimer’s Disease (AD) neuropathology hallmarks. Thiamine is a critical enzyme cofactor within the glycolytic metabolism network that is fundamentally required to sustain the bioenergetic and anabolic needs of all cells. The brain’s extensive requirement for glucose metabolism to satisfy its high energy demand makes it particularly vulnerable to TI mediated metabolic impairment. Congruent with established AD pathology, TI produces cerebral energy hypometabolism, inflammation, oxidative stress, and an increase in plaque formation within the hippocampus, cortex and thalamus. Thiamine or more specifically the activated cofactor, thiamine diphosphate (TDP) ensures the function of 3 key metabolic enzymes, PDH, α-KGDH, and TKT. A central feature for neuronal cell injury as a result of low cellular TDP levels is severe deficits in cerebral energy metabolism. Additionally, the activity of TKT, PDH, α-KGDH are significantly reduced in post-mortem Alzheimer’s patients and strongly correlate with dementia rating. Yet despite progress into the relationship between reduced thiamine levels and the neuropathology of AD, mechanistic insight is lacking. We have established that the metabolic dysfunction as a consequence of TI activates hypoxia inducible factor-1 alpha (HIF1α). This application will test the hypothesis that TI mediated metabolic activation of HIF1α initiates pro-apoptotic and amyloidogenic processes that produce the cellular and regional histological presentation of TI associated AD-neuropathology. We plan to test our central hypothesis and, thereby, accomplish the objective of this application by (1) Employing cell type selectivity of HIF1α KO we will reveal the contribution and relationship of astrocytic and neuronal HIF1α activity during TI on neurological damage. (2) Using a diseased based (3xTgAD) transgenic AD mouse model, we will establish HIF1α activation as an initiator for amyloidogenic activity and cognitive decline as a consequence of thiamine insufficiency. (3) Utilizing an unbiased transcriptomic analysis, we will establish the temporal impact of graded TI stress on HIF1α transcriptional activity within neurons and astrocytes. We propose to establish the contribution of HIF1α by using a combination of state-of-the-art methodology including RiboTag RNA-Seq and MR Imaging coupled with cell specific Cre-drivers for HIF1α knockout and triple transgenic AD mouse models. Establishing chronic activation of HIF1α in response to hypometabolism linked to micronutrient deficiency would provide a significant shift discerning AD etiology and suggest possible prophylactic strategies to limit age-related cognitive decline.