Dysregulation of tau phosphorylation in mouse brain during excitotoxic damage.
Glutamate receptor-mediated excitotoxicity is thought to contribute to the development of Alzheimer's disease (AD), but the underlying mechanism is unknown. In this study, we investigated the dynamic changes of tau phosphorylation and tau-related protein kinases and protein phosphatase 2A (PP2A) in the mouse brain during excitotoxicity induced by intraperitoneal injection of 20 mg/kg kainic acid (KA). We found that KA-induced excitotoxicity led to transient dephosphorylation of tau (within 6 hr post-injection), followed by sustained hyperphosphorylation of tau at multiple sites that are hyperphosphorylated in AD brain. The initial dephosphorylation of tau may result from activation of PP2A, and the sustained hyperphosphorylation may be due mainly to activation of cdk5 and down-regulation of PP2A during the later phase. Because abnormal hyperphosphorylation of tau plays a crucial role in neurodegeneration and in the formation of neurofibrillary tangles, our results suggest that glutamate receptor-mediated excitotoxicity might contribute to AD partially via promoting abnormal hyperphosphorylation of tau in AD brain.
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314-6399, USA.
Zhihou
Z
Liang
Fei
F
Liu
Khalid
K
Iqbal
Inge
I
Grundke-Iqbal
Cheng-Xin
CX
Gong
D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced* / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D047468:Immunoprecipitation / Q000379:methods; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D018690:Excitatory Amino Acid Agonists; D021122:Protein Subunits; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D007608:Kainic Acid