O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-β precursor protein (APP)

Jacobsen, Kristin; Iverfeldt, Kerstin

doi:10.1186/1750-1326-8-s1-p21

Cited by 15 publications

(19 citation statements)

References 2 publications

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“…It has been reported that O-GlcNAc modifies several important brain proteins, such as tau [39,40,51,52] and Aβ [53][54][55], which have been implicated in the pathogenesis of AD. We also detected O-GlcNAc-modified tau peptides (supplementary material, Table S3), but too many missing values occurred (i.e.…”

Section: S Wang Et Almentioning

confidence: 99%

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Wang

Yang

Petyuk

et al. 2017

The Journal of Pathology

110

126

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Protein modification by O-linked beta-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer’s disease, however detailed molecular characterization of this important protein posttranslational modification at proteome level has been highly challenging, due to its low stoichiometry and labile nature. Herein we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in post-mortem human brain tissues with and without Alzheimer’s disease using isobaric tandem mass tags labeling, chemoenzymatic photocleavage enrichment and liquid chromatography coupled to mass spectrometry. A total of 1,850 O-GlcNAc peptides covering 1,094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. One hundred and thirty one O-GlcNAc peptides covering 81 proteins were altered in Alzheimer’s brain as compared to controls (q <0.05). Moreover, alteration of O-GlcNAc peptide abundance could be attributed more to O-GlcNAcylation level than to protein level changes. The altered O-GlcNAcylated proteins belong to several structural and functional categories, including synaptic proteins, cytoskeleton proteins and memory-associated proteins. These findings suggest that dysregulation of O-GlcNAcylation of multiple brain proteins may be involved in the development of sporadic Alzheimer’s disease.

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Section: S Wang Et Almentioning

confidence: 99%

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Wang

Yang

Petyuk

et al. 2017

The Journal of Pathology

110

126

View full text Add to dashboard Cite

show abstract

“…It was largely proven that APP undergoes O-GlcNAcylation [43] and recent advances demonstrated that increased APP O-GlcNAc levels could switch its processing from the amyloidogenic pathway to the non-amyloidogenic via, thus reducing the production of Aβ plaques [73]. Since APP is encoded on chromosome 21, the role of O-GlcNAcylation in APP processing could be further exacerbated in DS neuropathology.…”

Section: The Aberrant O-glcnac/phosphorylation Ratio Of Tau and App Dmentioning

confidence: 99%

The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome

et al. 2021

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Protein O-GlcNAcylation is a nutrient-related post-translational modification that, since its discovery some 30 years ago, has been associated with the development of neurodegenerative diseases. As reported in Alzheimer’s disease (AD), flaws in the cerebral glucose uptake translate into reduced hexosamine biosynthetic pathway flux and subsequently lead to aberrant protein O-GlcNAcylation. Notably, the reduction of O-GlcNAcylated proteins involves also tau and APP, thus promoting their aberrant phosphorylation in AD brain and the onset of AD pathological markers. Down syndrome (DS) individuals are characterized by the early development of AD by the age of 60 and, although the two conditions present the same pathological hallmarks and share the alteration of many molecular mechanisms driving brain degeneration, no evidence has been sought on the implication of O-GlcNAcylation in DS pathology. Our study aimed to unravel for the first time the role of protein O-GlcNacylation in DS brain alterations positing the attention of potential trisomy-related mechanisms triggering the aberrant regulation of OGT/OGA cycle. We demonstrate the disruption of O-GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and confirm the relevance of O-GlcNAcylation in the appearance of AD hallmarks in the brain of a murine model of DS. Furthermore, we provide evidence for the neuroprotective effects of brain-targeted OGA inhibition. Indeed, the rescue of OGA activity was able to restore protein O-GlcNAcylation, and reduce AD-related hallmarks and decreased protein nitration, possibly as effect of induced autophagy.

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“…In a study using CSF from AD patients and nondemented controls, an increase in the short Ab fragments carrying the tyrosine-linked glycan was observed in AD patients. APP is also O-GlcNAcylated [30] and it was recently suggested that O-GlcNAcylation affects APP processing, resulting in increased levels of soluble APPa (sAPPa) and decreased Ab secretion [31]. It should be noted, however, that other proteins involved in AD pathology, e.g.…”

Section: App and Glycosylationmentioning

confidence: 99%

The role of protein glycosylation in Alzheimer disease

2013

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Glycosylation is one of the most common, and the most complex, forms of post-translational modification of proteins. This review serves to highlight the role of protein glycosylation in Alzheimer disease (AD), a topic that has not been thoroughly investigated, although glycosylation defects have been observed in AD patients. The major pathological hallmarks in AD are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are composed of phosphorylated tau, and the plaques are composed of amyloid b-peptide (Ab), which is generated from amyloid precursor protein (APP). Defects in glycosylation of APP, tau and other proteins have been reported in AD. Another interesting observation is that the two proteases required for the generation of amyloid b-peptide (Ab), i.e. c-secretase and b-secretase, also have roles in protein glycosylation. For instance, c-secretase and b-secretase affect the extent of complex N-glycosylation and sialylation of APP, respectively. These processes may be important in AD pathogenesis, as proper intracellular sorting, processing and export of APP are affected by how it is glycosylated. Furthermore, lack of one of the key components of c-secretase, presenilin, leads to defective glycosylation of many additional proteins that are related to AD pathogenesis and/or neuronal function, including nicastrin, reelin, butyrylcholinesterase, cholinesterase, neural cell adhesion molecule, v-ATPase, and tyrosine-related kinase B. Improved understanding of the effects of AD on protein glycosylation, and vice versa, may therefore be important for improving the diagnosis and treatment of AD patients.

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O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-β precursor protein (APP)

Cited by 15 publications

References 2 publications

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome

The role of protein glycosylation in Alzheimer disease

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