Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease

Abstract

It has been established for a long time that brain glucose metabolism is impaired in Alzheimer's disease. Recent studies have demonstrated that impaired brain glucose metabolism precedes the appearance of clinical symptoms, implying its active role in the development of Alzheimer's disease. However, the molecular mechanism by which this impairment contributes to the disease is not known. In this study, we demonstrated that protein O-GlcNAcylation, a common post-translational modification of nucleocytoplasmic proteins with beta-N-acetyl-glucosamine and a process regulated by glucose metabolism, was markedly decreased in Alzheimer's disease cerebrum. More importantly, the decrease in O-GlcNAc correlated negatively with phosphorylation at most phosphorylation sites of tau protein, which is known to play a crucial role in the neurofibrillary degeneration of Alzheimer's disease. We also found that hyperphosphorylated tau contained 4-fold less O-GlcNAc than non-hyperphosphorylated tau, demonstrating for the first time an inverse relationship between O-GlcNAcylation and phosphorylation of tau in the human brain. Downregulation of O-GlcNAcylation by knockdown of O-GlcNAc transferase with small hairpin RNA led to increased phosphorylation of tau in HEK-293 cells. Inhibition of the hexosamine biosynthesis pathway in rat brain resulted in decreased O-GlcNAcylation and increased phosphorylation of tau, which resembled changes of O-GlcNAcylation and phosphorylation of tau in rodent brains with decreased glucose metabolism induced by fasting, but not those in rat brains when protein phosphatase 2A was inhibited. Comparison of tau phosphorylation patterns under various conditions suggests that abnormal tau hyperphosphorylation in Alzheimer's disease brain may result from downregulation of both O-GlcNAcylation and protein phosphatase 2A. These findings suggest that impaired brain glucose metabolism leads to abnormal hyperphosphorylation of tau and neurofibrillary degeneration via downregulation of tau O-GlcNAcylation in Alzheimer's disease. Thus, restoration of brain tau O-GlcNAcylation and protein phosphatase 2A activity may offer promising therapeutic targets for treating Alzheimer's disease.

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

“…Glutamine:fructose‐6‐phosphate amidotransferase (GFAT) is the rate‐limiting enzyme of this pathway. We injected a specific inhibitor of GFAT, 6‐diazo‐5‐oxonorleucine (DON), intracerebroventricularly to downregulate O‐GlcNAcyaltion of proteins in rat brains (Liu et al ., 2009). We found that DON significantly suppressed protein O‐GlcNAcylation in rat brains (Fig.…”

“…The phosphorylation of tau at the PKA site―Ser214―was decreased, but at a non‐PKA site―Thr205― was increased (Fig. 5B), the latter of which is due to a different mechanism (Liu et al ., 2009). These results are consistent with the positive regulation of PKA activity by O‐GlcNAcylation.…”

“…Low glucose uptake causes downregulation of the O‐GlcNAcylation of brain proteins (Liu et al ., 2004, 2009). To study whether starvation‐induced lower brain glucose uptake suppresses PKA activity, resulting in decrease in the phosphorylation of PKA target substrates, we starved mice for 48 h and then assayed the phosphorylation of tau at Ser214 and CREB at Ser133.…”

“…In AD brain, O‐GlcNAcylation is downregulated as a result of impaired glucose uptake (Liu et al ., 2004, 2009). The phosphorylation of tau at other sites all increased significantly, but not of tau Ser214, suggesting downregulation of PKA activity.…”

“…O‐GlcNAcylation regulates the phosphorylation of the same protein in a reciprocal manner. We have previously found decreased O‐GlcNAcylation in AD brain as a result of lower glucose uptake (Liu et al ., 2004, 2009). However, whether the downregulation of O‐GlcNAc leads to cognitive decline in AD is not well known.…”