Repeated sleep deprivation decreases the flux into hexosamine biosynthetic pathway/O-GlcNAc cycling and aggravates Alzheimer’s disease neuropathology in adult zebrafish

This study investigated chronic and repeated sleep deprivation (RSD)-induced neuronal changes in hexosamine biosynthetic pathway/O-linked N-acetylglucosamine (HBP/O-GlcNAc) cycling of glucose metabolism and further explored the role of altered O-GlcNAc cycling in promoting neurodegeneration using an adult zebrafish model. RSD-triggered degenerative changes in the brain led to impairment of memory, neuroinflammation and amyloid beta (Aβ) accumulation. Metabolite profiling of RSD zebrafish brain revealed a significant decrease in glucose, indicating a potential association between RSD-induced neurodegeneration and dysregulated glucose metabolism. While RSD had no impact on overall O-GlcNAcylation levels in the hippocampus region, changes were observed in two O-GlcNAcylation-regulating enzymes, specifically, a decrease in O-GlcNAc transferase (OGT) and an increase in O-GlcNAcase (OGA). Glucosamine (GlcN) treatment induced an increase in O-GlcNAcylation and recovery of the OGT level that was decreased in the RSD group. In addition, GlcN reversed cognitive impairment by RSD. GlcN reduced neuroinflammation and attenuated Aβ accumulation induced by RSD. Repeated treatment of zebrafish with diazo-5-oxo-l-norleucine (DON), an inhibitor of HBP metabolism, resulted in cognitive dysfunction, neuroinflammation and Aβ accumulation, similar to the effects of RSD. The pathological changes induced by DON were restored to normal upon treatment with GlcN. Both the SD and DON-treated groups exhibited a common decrease in glutamate and γ-aminobutyric acid compared to the control group. Overexpression of OGT in zebrafish brain rescued RSD-induced neuronal dysfunction and neurodegeneration. RSD induced a decrease in O-GlcNAcylation of amyloid precursor protein and increase in β-secretase activity, which were reversed by GlcN treatment. Based on the collective findings, we propose that dysregulation of HBP and O-GlcNAc cycling in brain plays a crucial role in RSD-mediated progression of neurodegeneration and Alzheimer’s disease pathogenesis. Targeting of this pathway may, therefore, offer an effective regulatory approach for treatment of sleep-associated neurodegenerative disorders.