Hyperphosphorylation of Tau leads to neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD) and contributes to synaptic dysfunction underlying dementia. Reduction of Tau hyperphosphorylation is a therapeutic goal in AD. O-GlcNAc is an intracellular carbohydrate post- translational modification dynamically attached/removed by enzymes. Tau is modified by O-GlcNAc, and O-GlcNAc levels are reduced in human AD brain. O-GlcNAc competes with phosphorylation at specific serines/threonines, leading to the hypothesis that reduced O-GlcNAc in AD may contribute to Tau hyperphosphorylation. The 3XTg-AD mouse displays Abeta plaques and progressively increasing hyperphosphorylation of Tau that correlates with NFT burden. We've demonstrated specific decreases in O-GlcNAc modifications that correlate with Tau hyperphosphorylation in the 3XTg-AD mouse. We've demonstrated pharmacological elevation of in vivo brain O-GlcNAc levels for the first time using a novel inhibitor of the enzyme that hydrolyzes O-GlcNAc. This elevation of O- GlcNAc reduces hyperphosphorylation of Tau at the hyperphosphorylation epitope threonine 212 in the 3XTg-AD mouse. We will map human and mouse Tau O-GlcNAc sites and comprehensively determine the influence of pharmacological in vivo elevation of O-GlcNAc levels on specific Tau hyperphosphorylation events (through western blotting, mass spectrometry, and immunohistochemistry) and NFT burden in the 3XTg-AD mouse. This project will elucidate mechanistic interplay between O-GlcNAc and phosphorylation on Tau, demonstrate a novel component regulating Tau hyperphosphorylation in AD, and define enzymes that regulate O-GlcNAc levels as novel candidate therapeutic targets in AD.

Public Health Relevance

/Relevance Alzheimer's disease (AD) is the major cause of dementia. Tau hyperphosphorylation leading to neurofibrillary tangles contributes to neuronal dysfunction and degeneration in AD. This work will help establish O-GlcNAc as a novel mechanism regulating Tau hyperphosphorylation in AD, stimulate other researches seeking a molecular understanding of Tau pathology to entertain and further test the contribution of O-GlcNAc, and will generate novel therapeutic targets for reducing Tau hyperphosphorylation, which may improve the health of individuals with AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG033226-02
Application #
7769497
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Miller, Marilyn
Project Start
2009-03-01
Project End
2012-02-28
Budget Start
2010-03-15
Budget End
2012-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$150,717
Indirect Cost
Name
Drexel University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Skorobogatko, Yuliya; Landicho, Ashly; Chalkley, Robert J et al. (2014) O-linked ?-N-acetylglucosamine (O-GlcNAc) site thr-87 regulates synapsin I localization to synapses and size of the reserve pool of synaptic vesicles. J Biol Chem 289:3602-12
Zachara, Natasha E; Vosseller, Keith; Hart, Gerald W (2011) Detection and analysis of proteins modified by O-linked N-acetylglucosamine. Curr Protoc Protein Sci Chapter 12:Unit12.8
Zachara, Natasha E; Vosseller, Keith; Hart, Gerald W (2011) Detection and analysis of proteins modified by O-linked N-acetylglucosamine. Curr Protoc Mol Biol Chapter 17:Unit 17.6