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

Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.
Brain (Impact Factor: 9.2). 06/2009; 132(Pt 7):1820-32. DOI: 10.1093/brain/awp099
Source: PubMed


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.

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    • "xpected tau hyperphosphorylation (Oddo et al., 2003). To our knowledge, this is the first evidence that tau is hypo-O-GlcNAcylated in a mouse model of AD. Although increasing evidence suggests that abnormalities of O-GlcNAcylation play a role in the pathophysiology of AD, studies on O-GlcNAcylation in the AD brain have produced contrasting results.Liu et al. (2009)have found a reduced tau O-GlcNAcylation in brain tissue from AD patients, whereas increases in protein O-GlcNAcylation were found in two other reports (Griffith et al., 1995;Förster et al., 2014). There might be many explanations for the contrasting data obtained in the AD brain, including differences in the selected brain regions, samp"
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    ABSTRACT: Intracellular accumulation of hyperphosphorylated tau protein is linked to neuronal degeneration in Alzheimer's disease (AD). Mounting evidence suggests that tau phosphorylation and O-N-acetylglucosamine glycosylation (O-GlcNAcylation) are mutually exclusive post-translational modifications. O-GlcNAcylation depends on 3-5% of intracellular glucose that enters the hexosamine biosynthetic pathway. To our knowledge, the existence of an imbalance between tau phosphorylation and O-GlcNAcylation has not been reported in animal models of AD, as yet. Here, we used triple transgenic (3xTg-AD) mice at 12 months, an age at which hyperphosphorylated tau is already detected and associated with cognitive decline. In these mice, we showed that tau was hyperphosphorylated on both Ser396 and Thr205 in the hippocampus, and to a lower extent and exclusively on Thr205 in the frontal cortex. Tau O-GlcNAcylation, assessed in tau immunoprecipitates, was substantially reduced in the hippocampus of 3xTg-AD mice, with no changes in the frontal cortex or in the cerebellum. No changes in the expression of the three major enzymes involved in O-GlcNAcylation, i.e., glutamine fructose-6-phosphate amidotransferase, O-linked β-N-acetylglucosamine transferase, and O-GlcNAc hydrolase were found in the hippocampus of 3xTg-AD mice. These data demonstrate that an imbalance between tau phosphorylation and O-GlcNAcylation exists in AD mice, and strengthens the hypothesis that O-GlcNAcylation might be targeted by disease modifying drugs in AD.
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    • "The results with Ogt are potentially interesting, as it appears that Compound C may differentially repress Ogt at 5.5 mM, but not 0.5 mM (p = 0.067), although this did not yet reach statistical significance. Ogt has been linked to brain glucose metabolism, as well as insulin resistance [44, 45], and may have a unique role in the hypothalamus at different glucose concentrations. Moreover, Ogt levels and activity are increased in AgRP neurons during fasting [46] , as is corroborated by our results in the mHy- poE-37 neurons. "
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    • "We consider that if the accountability of mOGT in the brain damage, observed in patients with diabetes or at risk of developing AD, is established, several relevant points could be clarified. For example: 1) it would improve our comprehension of the diabetes-AD association; 2) it would help to understand the differences in the results found by various research groups (Butkinaree et al., 2010; Hart et al., 2011; Liu et al., 2009; Shin et al., 2011); 3) it would help to explain the origin of the neuropathological features associated with AD, but observed also in the brain of patients with dementia or diabetes alone; and 4) it could help to evaluate diabetic patients in a presymptomatic phase or those with insulin resistance but at risk of developing Alzheimer disease (Wirz et al., 2014). All this aimed at providing an adequate and early treatment to prevent the eventual development of AD. "
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    ABSTRACT: Diabetes mellitus (DM) is considered a risk factor for the development of Alzheimer disease (AD); however, how DM favors evolution of AD is still insufficiently understood. Hyperglycemia in DM is associated to an increase in mitochondrial reactive oxygen species (ROS) generation, as well as damage of hippocampal cells, reflected by changes in morphological and mitochondrial functionality. Similar mitochondrial damage has been observed when amyloid beta (Aβ) accumulates in the brain of AD patients. In DM, the excess of glucose in the brain induces higher activity of the hexosamine biosynthesis pathway (HBP), it synthesizes UDP-N-acetylglucosamine (UDP-GlcNAc), which is used by O-linked N-acetylglucosamine transferase (OGT) to catalyze O-GlcNAcylation of numerous proteins. Although O-GlcNAcylation plays an important role in maintaining structure and cellular functionality, chronic activity of this pathway has been associated with insulin resistance and hyperglycemia-induced glucose toxicity. Three different forms of OGT are known: nucleocytoplasmic (ncOGT), short (sOGT), and mitochondrial (mOGT). Previous reports showed that overexpression of ncOGT is not toxic to the cell; in contrast, overexpression of mOGT is associated with cellular apoptosis. In this work, we suggest that hyperglycemia in the diabetic patient could induce greater expression and activity of mOGT, modifying the structure and functionality of mitochondria in hippocampal cells, accelerating neuronal damage, and favoring the start of AD. In consequence, mOGT activity could be a key point for AD development in patients with DM.
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