Increased O-GlcNAc levels correlate with decreased O-GlcNAcase levels in Alzheimer disease brain

Förster, Sarah; Welleford, Andrew; Triplett, Judy C.; Sultana, Rukhsana; Schmitz, Brigitte; Butterfield, D. Allan

doi:10.1016/j.bbadis.2014.05.014

Cited by 59 publications

(45 citation statements)

References 50 publications

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“…In light of the marked neurodegenerative phenotypes of OGT cKO mice, we examined whether human AD brains had reduced levels of OGT expression at the cellular level. Previously, both increases and decreases in O-GlcNAcylated proteins had been reported in the cerebral cortex of AD brains compared with control individuals (29,30). Notably, we found that cortical neurons from severe AD patients (Braak stage VI) displayed a 1.6-fold decrease in OGT protein levels compared with age-and sex-matched controls (Fig.…”

Section: Loss Of O-glcnacylation In Ogt Cko Mice Leads To Progressivesupporting

confidence: 62%

Loss of O -GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration

Wang

Jensen

Rexach

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

158

137

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O-GlcNAc glycosylation (or O-GlcNAcylation) is a dynamic, inducible posttranslational modification found on proteins associated with neurodegenerative diseases such as α-synuclein, amyloid precursor protein, and tau. Deletion of the O-GlcNAc transferase (ogt) gene responsible for the modification causes early postnatal lethality in mice, complicating efforts to study O-GlcNAcylation in mature neurons and to understand its roles in disease. Here, we report that forebrain-specific loss of OGT in adult mice leads to progressive neurodegeneration, including widespread neuronal cell death, neuroinflammation, increased production of hyperphosphorylated tau and amyloidogenic Aβ-peptides, and memory deficits. Furthermore, we show that human cortical brain tissue from Alzheimer’s disease patients has significantly reduced levels of OGT protein expression compared with cortical tissue from control individuals. Together, these studies indicate that O-GlcNAcylation regulates pathways critical for the maintenance of neuronal health and suggest that dysfunctional O-GlcNAc signaling may be an important contributor to neurodegenerative diseases.

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Section: Loss Of O-glcnacylation In Ogt Cko Mice Leads To Progressivesupporting

confidence: 62%

Loss of O -GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration

Wang

Jensen

Rexach

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

158

137

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“…OGT and O-GlcNAcase (OGA) enzymes facilitate O-GlcNAc cycling, and levels of GlcNAc have also been observed to be increased in the parietal lobe of AD brains [47]. Appropriately, OGA inhibitors have been tested for treating AD with promising preliminary results [48], prompting further investigation into targeting OGT for AD treatment.…”

Section: Down-regulated Superoxide Dismutase 1 (Sod1) Gene Encodes Fomentioning

confidence: 99%

A Meta-Analysis of Alzheimer’s Disease Brain Transcriptomic Data

Patel

Dobson

Newhouse

2018

Preprint

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BackgroundMicroarray technologies have identified imbalances in the expression of specific genes and biological pathways in Alzheimer's disease (AD) brains. However, there is a lack of reproducibility across individual AD studies, and many related neurogenerative and mental health disorders exhibit similar perturbations. We are yet to identify robust transcriptomic changes specific to AD brains. This study meta-analysed publicly available brain-related disorders along with healthy cognitive individuals to decipher common and AD-specific brain transcriptomic changes. Methods and ResultsTwenty-two AD, eight Schizophrenia, five Bipolar Disorder, four Huntington's disease, two Major Depressive Disorder and one Parkinson's disease dataset totalling 2667 samples and mapping to four different brain regions (Temporal lobe, Frontal lobe, Parietal lobe and Cerebellum) were analysed. Differential expression analysis was performed independently in each dataset, followed by metaanalysis using a combining p-value method known as Adaptively Weighted with One-sided Correction. This identified 323, 435, 1023 and 828 differentially expressed genes specific to the AD temporal lobe, frontal lobe, parietal lobe and cerebellum brain regions respectively. Seven of these genes were consistently perturbed across all AD brain regions and are considered disease-specific, while twenty-two genes are perturbed specifically in AD brain regions affected by both plaques and tangles, suggesting involvement in AD neuropathology. Biological pathways involved in the "metabolism of proteins" and viral components were significantly enriched across AD brains. ConclusionWe identify specific transcriptomic changes in AD brains which could make a significant contribution towards the understanding of AD disease mechanisms and provides new therapeutic targets.providing an opportunity to identify imbalances in the expression of specific genes and biological pathways. However, microarray reproducibility has always been questionable, with replication of differentially expressed genes (DEG's) very poor [6]. For example, two independent microarray transcriptomic studies performed differential expression analysis in the hippocampus of AD brains. The first study by Miller et al. identified 600 DEG's [7], and a similar study by Hokama et al. identified 1071 DEG's [8]. An overlap of 105 DEG's exist between the two studies; however, after accounting for multiple testing, no gene was replicated between the two studies. The Miller study consisted of 7 AD and 10 control subjects expression profiled on the Affymetrix platform while the Hakoma study consisted of 31 AD and 32 control subjects expression profiled on the Illumina platform. Replication between the Illumina and Affymetrix platform has been shown to be generally very high [9];therefore, the lack of replication between the two studies is probably down to a range of other factors including low statistical power, sampling bias and disease heterogeneity.Unlike DEG's, replication of the molecular changes at a pathwa...

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“…The hypothesis that impaired O-GlcNAc levels might contribute to the progression of AD has been bolstered by studies showing that brain tissue from AD patients has lower O-GlcNAc levels when considering postmortem delay (46) and, more recently, in a different patient population in which decreased overall cytosolic O-GlcNAc levels were observed in the frontal cortex but not in the cerebellum (61). However, other studies using different analytic tools have suggested that O-GlcNAc levels in fact increase either generally (62) or within the detergent-insoluble fraction of AD brain tissue from regions other than the cerebellum (63). More rigorous studies of human tissues, ideally coupled with immunohistochemical analysis of O-GlcNAc within neurons, are needed to unambiguously clarify this issue.…”

Section: Nutrient-mediated Regulation Of O-glcnacmentioning

confidence: 99%