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J Alzheimers Dis. 2006 Mar;9(1):1-12.

Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation.

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Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA.


Neurofibrillary degeneration characterized by abnormal hyperphosphorylation and aggregation of tau in affected neurons is directly associated with dementia symptoms and plays a pivotal role in the pathogenesis of Alzheimer disease (AD) and related tauopathies. It is well established that brain glucose uptake/metabolism is impaired in AD, but how this impairment contributes to the disease is unknown. We recently found that tau in human brain is also modified by O-GlcNAcylation in addition to phosphorylation and that the former negatively regulates the latter. On the basis of these findings, we propose a novel hypothesis that the impaired glucose uptake/metabolism contributes to AD by facilitating abnormal hyperphosphorylation of tau. Further studies of this mechanism are likely to offer a novel therapeutic target for preventing and treating AD.

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