Threonine 576 residue of amyloid-β precursor protein regulates its trafficking and processing

Chun, Yoon S.; Kwon, Oh-Hyun; Oh, Hyun Geun; Kim, Tae‐Wan; McIntire, Laura Beth; Park, Myoung Kyu; Chung, Sungkwon

doi:10.1016/j.bbrc.2015.10.037

Cited by 10 publications

(8 citation statements)

References 24 publications

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“…In addition, O-GlcNAcylation status of α-, β- and γ-secretases may also be implicated in OGN inhibitor-induced alteration of APP processing (Dias et al, 2009 ; Tarrant et al, 2012 ). Recently, Chun et al ( 2015a ) showed that the APP O-glycosylated site mutant (Thr576Ala) reduced APP expression on cell surface but increased its accumulation in the early endosome, leading to the increase of Aβ generation. It indicates that APP glycosylation does affect its processing and Aβ generation, which is associated with the alteration of APP trafficking.…”

Section: App Modifications and Trafficking In Aβ Generationmentioning

confidence: 99%

Modifications and Trafficking of APP in the Pathogenesis of Alzheimer’s Disease

Wang

Zhou

et al. 2017

Front. Mol. Neurosci.

120

102

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Alzheimer’s disease (AD), the most common neurodegenerative disorder, is the leading cause of dementia. Neuritic plaque, one of the major characteristics of AD neuropathology, mainly consists of amyloid β (Aβ) protein. Aβ is derived from amyloid precursor protein (APP) by sequential cleavages of β- and γ-secretase. Although APP upregulation can promote AD pathogenesis by facilitating Aβ production, growing evidence indicates that aberrant post-translational modifications and trafficking of APP play a pivotal role in AD pathogenesis by dysregulating APP processing and Aβ generation. In this report, we reviewed the current knowledge of APP modifications and trafficking as well as their role in APP processing. More importantly, we discussed the effect of aberrant APP modifications and trafficking on Aβ generation and the underlying mechanisms, which may provide novel strategies for drug development in AD.

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Section: App Modifications and Trafficking In Aβ Generationmentioning

confidence: 99%

Modifications and Trafficking of APP in the Pathogenesis of Alzheimer’s Disease

Wang

Zhou

et al. 2017

Front. Mol. Neurosci.

120

102

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“…It has been shown that blocking the activity of mannosidase hampers the production of hybrid and complex forms of N glycan which affects APP transport and other proteins to the synaptic membrane ( Bieberich, 2014 ). Recently site-directed mutagenesis approach has shown that specific O-glycosylation at Thr576, directs its transport toward the plasma membrane and the subsequent endocytosis of APP elevates Aβ levels ( Chun et al, 2015b ). Treatment of experimental 5XFAD mice with a small molecule inhibitor blocking the glycosylation of gamma secretase lead to reduced production of AB peptides, thus slowing the progression of neuroinflammation followed by recovery in memory impairments ( Kim et al, 2013 ).…”

Section: Post-translational Modifications In Alzheimer’s Diseasementioning

confidence: 99%

Clinical relevance of biomarkers, new therapeutic approaches, and role of post-translational modifications in the pathogenesis of Alzheimer’s disease

Mumtaz

Ayaz

Khan

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a neurodegenerative disorder that causes progressive loss of cognitive functions like thinking, memory, reasoning, behavioral abilities, and social skills thus affecting the ability of a person to perform normal daily functions independently. There is no definitive cure for this disease, and treatment options available for the management of the disease are not very effective as well. Based on histopathology, AD is characterized by the accumulation of insoluble deposits of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although several molecular events contribute to the formation of these insoluble deposits, the aberrant post-translational modifications (PTMs) of AD-related proteins (like APP, Aβ, tau, and BACE1) are also known to be involved in the onset and progression of this disease. However, early diagnosis of the disease as well as the development of effective therapeutic approaches is impeded by lack of proper clinical biomarkers. In this review, we summarized the current status and clinical relevance of biomarkers from cerebrospinal fluid (CSF), blood and extracellular vesicles involved in onset and progression of AD. Moreover, we highlight the effects of several PTMs on the AD-related proteins, and provide an insight how these modifications impact the structure and function of proteins leading to AD pathology. Finally, for disease-modifying therapeutics, novel approaches, and targets are discussed for the successful treatment and management of AD.

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“…O-GlcNAcylation has also been associated with APP processing [81,84]. O-GlcNAcylation at Thr576 regulates the trafficking of APP to the cell surface and decreases the endocytosis rate.…”

Section: O-glycosylation and Aβ Productionmentioning

confidence: 99%

The Role of APP O-Glycosylation in Alzheimer’s Disease

Akasaka‐Manya

Manya

2020

Biomolecules

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The number of people with dementia is increasing rapidly due to the increase in the aging population. Alzheimer’s disease (AD) is a type of neurodegenerative dementia caused by the accumulation of abnormal proteins. Genetic mutations, smoking, and several other factors have been reported as causes of AD, but alterations in glycans have recently been demonstrated to play a role in AD. Amyloid-β (Aβ), a cleaved fragment of APP, is the source of senile plaque, a pathological feature of AD. APP has been reported to undergo N- and O-glycosylation, and several Polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) have been shown to have catalytic activity for the transfer of GalNAc to APP. Since O-glycosylation in the proximity of a cleavage site in many proteins has been reported to be involved in protein processing, O-glycans may affect the cleavage of APP during the Aβ production process. In this report, we describe new findings on the O-glycosylation of APP and Aβ production.

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Threonine 576 residue of amyloid-β precursor protein regulates its trafficking and processing

Cited by 10 publications

References 24 publications

Modifications and Trafficking of APP in the Pathogenesis of Alzheimer’s Disease

Modifications and Trafficking of APP in the Pathogenesis of Alzheimer’s Disease

Clinical relevance of biomarkers, new therapeutic approaches, and role of post-translational modifications in the pathogenesis of Alzheimer’s disease

The Role of APP O-Glycosylation in Alzheimer’s Disease

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