Journal
AGING CELL
Volume 15, Issue 3, Pages 455-464Publisher
WILEY
DOI: 10.1111/acel.12449
Keywords
Alzheimer's disease; learning and memory; O-GlcNAcylation; protein kinase A
Categories
Funding
- New York State Office for People with Developmental Disabilities (OPWDD)
- Nantong University
- U.S. Alzheimer's Association [2010-IIRG-173154, DSAD-15-363172, 2015-NIRG-339945]
- National Natural Science Foundation of China [81030059, 81000496]
- Neural Regeneration Co-innovation Center of Jiangsu Province
- Priority Academic Program Development of Jiangsu Higher Education institutions (PAPD)
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Alzheimer's disease (AD) is characterized clinically by memory loss and cognitive decline. Protein kinase A (PKA)-CREB signaling plays a critical role in learning and memory. It is known that glucose uptake and O-GlcNAcylation are reduced in AD brain. In this study, we found that PKA catalytic subunits (PKAcs) were posttranslationally modified by O-linked N-acetylglucosamine (O-GlcNAc). O-GlcNAcylation regulated the subcellular location of PKAc and PKAc and enhanced their kinase activity. Upregulation of O-GlcNAcylation in metabolically active rat brain slices by O-(2-acetamido-2-deoxy-d-glucopyranosylidenamino) N-phenylcarbamate (PUGNAc), an inhibitor of N-acetylglucosaminidase, increased the phosphorylation of tau at the PKA site, Ser214, but not at the non-PKA site, Thr205. In contrast, in rat and mouse brains, downregulation of O-GlcNAcylation caused decreases in the phosphorylation of CREB at Ser133 and of tau at Ser214, but not at Thr205. Reduction in O-GlcNAcylation through intracerebroventricular injection of 6-diazo-5-oxo-l-norleucine (DON), the inhibitor of glutamine fructose-6-phosphate amidotransferase, suppressed PKA-CREB signaling and impaired learning and memory in mice. These results indicate that in addition to cAMP and phosphorylation, O-GlcNAcylation is a novel mechanism that regulates PKA-CREB signaling. Downregulation of O-GlcNAcylation suppresses PKA-CREB signaling and consequently causes learning and memory deficits in AD.
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