Alzheimer's disease is associated with disruption in thiamin transport physiology: A potential role for neuroinflammation.

Kalidas Ramamoorthy, Ryan Yoshimura, Saleh Al-Juburi, Kasin Y Anandam, Rubina Kapadia, Amal Alachkar, Geoffrey W Abbott, Hamid M Said

Neurobiology of disease 2022 Sep

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Alzheimer's disease (AD) is a neurodegenerative disease characterized by Amyloid-β peptide (Aβ) containing plaques and cognitive deficits. The pathophysiology of AD also involves neuroinflammation. Vitamin B1 (thiamin) is indispensable for normal cellular energy metabolism. Thiamin homeostasis is altered in AD, and its deficiency is known to aggravate AD pathology. Little, however, is known about possible alterations in level of expression of thiamin transporters-1 and -2 (THTR-1 and -2) in the brain of AD, and whether pro-inflammatory cytokines affect thiamin uptake by brain cells. We addressed these issues using brain tissue samples [prefrontal cortex (PFC) and hippocampus (HIP)] from AD patients and from 5XFAD mouse model of AD, together with cultured human neuroblastoma SH-SY5Y cells as model. Our results revealed a significantly lower expression of both THTR-1 and THTR-2 in the PFC and HIP of AD patients and 5XFAD mouse model of AD compared to appropriate normal controls. Further, we found that exposure of the SH-SY5Y cells to pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) led to a significant inhibition in thiamin uptake. Focusing on IL-1β, we found the inhibition in thiamin uptake to be time-dependent and reversible; it was also associated with a substantial reduction in expression of THTR-1 (but not THTR-2) protein and mRNA as well as a decrease in promoter activity of the SLC19A2 gene (which encodes THTR-1). Finally, using transcriptomic analysis, we found that thiamin availability in SH-SY5Y cells caused changes in the expression of genes relevant to AD pathways. These studies demonstrate, for the first time, that thiamin transport physiology/molecular biology parameters are negatively impacted in AD brain and that pro-inflammatory cytokines inhibit thiamin uptake by neuroblastoma cells. The results also support a possible role for thiamin in the pathophysiology of AD. Copyright © 2022. Published by Elsevier Inc.

Citation

Kalidas Ramamoorthy, Ryan Yoshimura, Saleh Al-Juburi, Kasin Y Anandam, Rubina Kapadia, Amal Alachkar, Geoffrey W Abbott, Hamid M Said. Alzheimer's disease is associated with disruption in thiamin transport physiology: A potential role for neuroinflammation. Neurobiology of disease. 2022 Sep;171:105799