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

Jacobsen, Kristin; Iverfeldt, Kerstin

doi:10.1016/j.bbrc.2010.12.080

Cited by 88 publications

(62 citation statements)

References 30 publications

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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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Section: App and Glycosylationmentioning

confidence: 99%

The role of protein glycosylation in Alzheimer disease

2013

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“…APP, the precursor protein to Aβ, is O-GlcNAc-modified although the importance of this modification remained elusive for many years (Jacobsen and Iverfeldt 2011). It was later demonstrated that inhibiting O-GlcNAcase with PUGNAc or reducing the expression of O-GlcNAcase (siRNA) increased the amount of APP O-GlcNAcylation and non-amyloidogenic α-secretase processing (Jacobsen and Iverfeldt 2011). This has further downstream effects such as increasing levels of the neuroprotective sAPPα fragment, which reduces Aβ secretion and suggests a protective role for O-GlcNAc (Kim et al 2012).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

Groves

Lee

Yildirir

et al. 2013

Cell Stress and Chaperones

119

112

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O-linked N-acetyl-β-D-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (OGlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced OGlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer's and Parkinson's diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.

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“…OGT participates in specialized neuronal processes, including activity-dependent transcription and long-term depression via regulation of cAMP-responsive element binding protein (CREB) (5) and the AMPA receptor GluA2 subunit (12), respectively. O-GlcNAcylation also has been implicated in neurodegenerative diseases and is reported on proteins such as amyloid precursor protein (APP) (13), α-synuclein (14), neurofilament M (NFM) (15), and tau (16). Several studies have suggested neuroprotective roles for the modification.…”

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confidence: 99%

“…For example, increasing global levels of O-GlcNAcylation in neurons decreased the production of pathological forms of NFM and tau (15,16) and directly inhibited the aggregation of both tau (17) and α-synuclein (18). Glycosylation of nicastrin, a component of the γ-secretase complex, enhanced the nonamyloidogenic processing of APP (13,19). Moreover, raising O-GlcNAcylation levels by pharmacological inhibition of OGA attenuated amyloid-β deposition, tau phosphorylation, motor deficits, and memory impairments in certain AD mouse models (17,19).…”

mentioning

confidence: 99%

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

Cited by 88 publications

References 30 publications

The role of protein glycosylation in Alzheimer disease

The role of protein glycosylation in Alzheimer disease

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

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

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