O-GlcNAcylation of Amyloid-beta Protein Precursor by Insulin Signaling Reduces Amyloid-beta Production
- Authors
- Kwon, OH[Kwon, Oh Hoon]; Cho, YY[Cho, Yoon Young]; Kim, TW[Kim, Tae-Wan]; Chung, S[Chung, Sungkwon]
- Issue Date
- 2019
- Publisher
- IOS PRESS
- Keywords
- Alzheimer' s disease; amyloid-beta; amyloid-beta protein precursor; insulin; O-GlcNAcylation
- Citation
- JOURNAL OF ALZHEIMERS DISEASE, v.69, no.4, pp.1195 - 1211
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF ALZHEIMERS DISEASE
- Volume
- 69
- Number
- 4
- Start Page
- 1195
- End Page
- 1211
- URI
- https://scholarworks.bwise.kr/skku/handle/2021.sw.skku/16147
- DOI
- 10.3233/JAD-190060
- ISSN
- 1387-2877
- Abstract
- Alzheimer's disease (AD) is caused by the accumulation of neurotoxic amyloid-beta (A beta) peptides. A beta is derived from amyloid-beta protein precursor (A beta PP). In the non-amyloidogenic pathway, A beta PP is cleaved by alpha-secretase and gamma-secretase at the plasma membrane, excluding A beta production. Alternatively, A beta PP in the plasma membrane is internalized via endocytosis, and delivered to early endosomes and lysosomes, where it is cleaved by beta-secretase and gamma-secretase. Recent studies have shown that insulin in the periphery crosses the blood-brain barrier, and plays important roles in the brain. Furthermore, impaired insulin signaling has been linked to the progression of AD, and intranasal insulin administration improves memory impairments and cognition. However, the underlying molecular mechanisms of insulin treatment remain largely unknown. To investigate the effects of insulin on A beta PP processing, we tested the effects of insulin on neuroblastoma SH-SY5Y cells overexpressing A beta PP, and cultured rat cortical neurons. We found that insulin increased the level of cell surface A beta PP, decreasing the endocytosis rate of A beta PP. Insulin reduced A beta generation through upregulation of A beta PP O-GlcNAcylation via Akt insulin signaling. Our present data suggest that insulin affects A beta production by regulating A beta PP processing through A beta PP O-GlcNAcylation. These results provide mechanistic insight into the beneficial effects of insulin, and a possible link between insulin deficient diabetes and cerebral amyloidosis in the pathogenesis of AD.
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- Appears in
Collections - Medicine > Department of Medicine > 1. Journal Articles
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