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J Alzheimers Dis. 2019;69(4):1195-1211. doi: 10.3233/JAD-190060.

O-GlcNAcylation of Amyloid-β Protein Precursor by Insulin Signaling Reduces Amyloid-β Production.

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Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea.
Department of Pathology and Cell Biology, and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.


Alzheimer's disease (AD) is caused by the accumulation of neurotoxic amyloid-β (Aβ) peptides. Aβ is derived from amyloid-β protein precursor (AβPP). In the non-amyloidogenic pathway, AβPP is cleaved by α-secretase and γ-secretase at the plasma membrane, excluding Aβ production. Alternatively, AβPP in the plasma membrane is internalized via endocytosis, and delivered to early endosomes and lysosomes, where it is cleaved by β-secretase and γ-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 AβPP processing, we tested the effects of insulin on neuroblastoma SH-SY5Y cells overexpressing AβPP, and cultured rat cortical neurons. We found that insulin increased the level of cell surface AβPP, decreasing the endocytosis rate of AβPP. Insulin reduced Aβ generation through upregulation of AβPP O-GlcNAcylation via Akt insulin signaling. Our present data suggest that insulin affects Aβ production by regulating AβPP processing through AβPP 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.


Alzheimer’s disease; O-GlcNAcylation; amyloid-β ; amyloid-β protein precursor; insulin


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