Alzheimer’s disease (AD) is a neurodegenerative disease characterized by Amyloid-β peptide (Aβ)- containing plaques, neurofibrillary tangles and cognitive deficits. Mitochondrial dysfunction, oxidative stress and diminished glucose metabolism are consistent features of AD. The pathophysiology of AD also includes neuroinflammation, which is associated with an elevation of pro-inflammatory cytokines (e. g., TNF-α, interleukin 1β). Thiamine (vitamin B1; also referred to as the “energy vitamin”) is indispensable for normal oxidative energy metabolism and ATP production in the mitochondria; it also plays an important role in reducing cellular oxidative stress. Thus, deficiency of thiamine at the cellular level leads to impairment in oxidative energy metabolism, a decrease in cellular ATP level, and to a propensity for oxidative stress; it also leads to impairment in the function/structure of mitochondria. Compelling evidence exists suggesting that thiamine homeostasis is altered in AD, and that deficiency of the vitamin aggravates disease pathology. Brain cells obtain thiamin from the blood via a specialized carriermediated process that involves thiamine transporter-1 and -2 (products of the SLC19A2 and SLC19A3 genes, respectively). Once internalized, thiamine is enzymatically converted to thiamin pyrophosphate (TPP) then transported into mitochondria via another specialized carrier-mediated process that involves the mitochondrial TPP transporter (MTPPT; product of the SLC25A19 gene). Recent preliminary studies from our laboratory related to the parent R01 grant have shown that in two different human/animal tissues (the pancreas and the intestine), prolonged exposure to pro-inflammatory cytokines leads to a significant inhibition in cellular thiamin uptake as well as in transport of TPP into mitochondria. Given these data, we hypothesize here that thiamine uptake by brain cells and subsequent transport of TPP into their mitochondria is similarly impacted by chronic exposure to proinflammatory cytokines. This in turn leads to deficient/suboptimal cellular thiamine levels and impairment in oxidative metabolism/ATP production, an increase in oxidative stress, and abnormality in function/structure of mitochondria, which may contribute to the pathogenesis of AD. We will test this hypothesis by accomplishing the following Specific Aims: 1) Investigate possible changes in level of expression of the thiamine transporters SLC19A2, SLC19A3 and SLC25A19 in different regions of the brains of AD patients; 2) Examine the effect of exposure of brain cells to pro-inflammatory cytokines on cellular thiamine uptake and transport of TPP into their mitochondria and determine the molecular mechanisms involved; 3) Determine changes in the level of expression and activity of THTR-1, THTR-2 and MTPPT in the brain of mouse models of AD.