Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation.
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.
Gong
Cheng-Xin
CX
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA. cxgong@ultinet.net
Liu
Fei
F
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D000118:Acetylglucosaminidase / Q000378:metabolism; D000215:Acylation; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D005947:Glucose / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D001619:beta-N-Acetylhexosaminidases; D016875:tau Proteins / Q000378:metabolism*
D009097:Multienzyme Complexes; D016875:tau Proteins; D051548:Histone Acetyltransferases; C110628:hexosaminidase C; D000118:Acetylglucosaminidase; D001619:beta-N-Acetylhexosaminidases; D005947:Glucose