O‐GlcNAcylation modulates GLUT1 levels at the blood‐brain barrier. (20th December 2022)

• Record Type: Journal Article
• Authors: Saiyasit, Napatsorn; Bauman, Allison J.; Nelson, Amy R.
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.066669
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Glucose transporter 1 (GLUT1) at the blood‐brain barrier (BBB) is essential for glucose uptake into the brain. Previous studies have shown that GLUT1 levels are reduced at the BBB in Alzheimer's disease (AD) post‐mortem brain, and perhaps explains the decreased glucose utilization observed in AD (Sweeney et al., Nat Rev Neurol, 2018). Individuals with a genetic reduction of GLUT1, known as GLUT1‐deficiency syndrome, were treated with increased blood glucose with no long‐lasting increase in brain glucose. Diabetes is a risk factor for AD and AD is sometimes referred to as Type‐3 diabetes due to elevated blood glucose levels. Taken together, these ideas provoked us to investigate connections between glucose and GLUT1 levels. Here, we tested if the glucose‐dependent post‐translational modification, O‐linked‐N‐acetylglucosaminylation (O‐GlcNAcylation), is the missing link. We hypothesized that increasing glucose concentrations will elevate O‐GlcNAcylation and decrease GLUT1 levels at the BBB. Furthermore, previous studies have shown that decreased GLUT1 levels result in reduced levels of the low‐density lipoprotein receptor‐related protein‐1 (LRP‐1) (Winkler, Nat Neurosci, 2015). Thus, we also are determining if altering glucose levels not only changes GLUT1 levels, but also other key BBB receptors implicated in AD. Methods: Mouse brain endothelial (bEnd.3) cells were treated with vehicle (glucose 5.6 mmol), DMSO, the O‐GlcNAcase inhibitor Thiamet‐G (TMG, 1 µM), or the O‐GlcNAc transferase inhibitor OSMI‐1 (20 µM), for 24 and 48 hours. Next, the protein expression of O‐GlcNAc and GLUT1 were measured by western blot. Results: As previously reported, TMG increased and OSMI‐1 decreased O‐GlcNAcylation at both 24 and 48 h, compared to vehicle. Notably, TMG treatment significantly reduced and OSMI‐1 increased GLUT1 expression at both time points. Conclusion: GLUT1 levels are modulated through O‐GlcNAcylation at BBB. When blood glucose levels are high, O‐GlcNAcylation will be high, thereby reducing GLUT1 at the BBB and brain glucose uptake. This is likely a homeostatic mechanism to prevent spikes in brain glucose levels when blood sugar levels are elevated.