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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Available from: Cheng-Xin Gong, Oct 03, 2015
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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.
    Experimental Gerontology 08/2014; 58. DOI:10.1016/j.exger.2014.08.008 · 3.49 Impact Factor
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    • "Up to now, the causes leading to elevated tau phosphorylation levels are only partially resolved: tau kinases are upregulated in brains from AD patients, while the expression of tau phosphatases is reduced (Patrick et al, 1999; Rudrabhatla & Pant, 2011). Further, elevated Ab levels and reduced O-GlcNAcetylation of tau have been described to be causative of tau hyperphosphorylation (Liu et al, 2009). "
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    ABSTRACT: Sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but no clear disease-initiating mechanism is known. Aβ deposits and neuronal tangles composed of hyperphosphorylated tau are characteristic for AD. Here, we analyze the contribution of microRNA-125b (miR-125b), which is elevated in AD. In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains. These data implicate miR-125b in the pathogenesis of AD by promoting pathological tau phosphorylation.
    The EMBO Journal 07/2014; 33(15). DOI:10.15252/embj.201387576 · 10.43 Impact Factor
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    • "We previously showed that altered tau O-GlcNAcylation , an O-linked post-translational modification of nucleocytoplasmic proteins by the monosaccharide β-Nacetylglucosamine (GlcNAc), links the impairment of brain glucose metabolism to tau hyperphosphorylation [124] [125] [126] . "
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    ABSTRACT: Contrary to the previous belief that insulin does not act in the brain, studies in the last three decades have demonstrated important roles of insulin and insulin signal transduction in various functions of the central nervous system. Deregulated brain insulin signaling and its role in molecular pathogenesis have recently been reported in Alzheimer's disease (AD). In this article, we review the roles of brain insulin signaling in memory and cognition, the metabolism of amyloid β precursor protein, and tau phosphorylation. We further discuss deficiencies of brain insulin signaling and glucose metabolism, their roles in the development of AD, and recent studies that target the brain insulin signaling pathway for the treatment of AD. It is clear now that deregulation of brain insulin signaling plays an important role in the development of sporadic AD. The brain insulin signaling pathway also offers a promising therapeutic target for treating AD and probably other neurodegenerative disorders.
    Neuroscience Bulletin 03/2014; 30(2). DOI:10.1007/s12264-013-1408-x · 2.51 Impact Factor
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