科研之友
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摘要
The hypothesis that amyloid pathology precedes and induces the tau pathology of Alzheimer's disease is experimentally supported hem through the identification of GSK-3 isozymes as a major link in the signaling pathway from amyloid to tau pathology. This study compares two novel bigenic mouse models: APP-V717I x Tau-P301L mice with combined amyloid and tau pathology and GSK-3 beta x Tau-P301L mice with tauopathy only. Extensive and remarkable parallels were observed between these strains including 1) aggravation of tauopathy with highly fibrillar tangles in the hippocampus and cortex, 2) prolonged survival correlated to alleviated brainstem tauopathy; 3) development of severe cognitive and behavioral defects in young adults before the onset of amyloid deposition or tauopathy, and 4) presence of pathological phosphoepitopes of tau, including the characteristic GSK-3 beta motif at S396/S404. Both GSK-3 isozymes were activated in the brain of parental APP-V717I amyloid mice, even at a young age when cognitive and behavioral defects are evident but before amyloid. deposition. The data indicate that amyloid induces tauopathy through activation of GSK-3 and suggest a role for the kinase in maintaining the functional integrity of adult neurons.
- 出版日期2008-3
