Amyloid activates GSK-3b to aggravate neuronal Tauopathy in bigenic mice (The American Journal of Pathology, 2008, 172:786-798)

報告日期: 2008/06/13
報告時間: 15:10/16:00
報告學生: 李竹菀
講評老師: 黃阿敏
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/970613-1.pdf

Amyloid Activates GSK-3b to Aggravate Neuronal Tauopathy in Bigenic Mice

 

The American Journal of Pathology, 172 (2008) 786-798

 

Speaker: 李竹菀 

Commentator: 黃阿敏 老師  

Time: 06/13/2008 15:10~16:00

Place: Room 602

 

Alzheimer’s disease (AD) is characterized pathologically by extracellular amyloid plaques and intracellular neurofibrillary tangles. The major content of amyloid plaques is b-amyloid (Ab) peptide which is derived from its precursor protein, the APP; whereas neurofibrillary tangles are associated with hyperphosphorylated tau protein. Previous studies indicated that mice overexpressed mutant APP and mutant Tau had more neurofibrillary tangles than those mice overexpressed mutant Tau alone, suggesting APP/Aβ promotes tau hyperphosphorylation and subsequent the formation of neurofibrillary tangles. However, the activation pathways and molecular changes triggered by Aβ that drive the phosphorylation of protein tau into its eventual aggregation into tangles remain unclear. Glycogen synthase kinase-3b (GSK-3b) has a long history in AD as one of the tau kinases based on experiments with isolated recombinant proteins and cellular models. Furthermore, GSK-3b is co-localized with disease related structures in AD brain. Therefore, the authors hypothesized that Aβ peptides induced tau pathology observed in AD brain is through the activation of GSK-3 b. This study use two novel bigenic mouse models: APP-V717I×Tau-P301L (biAT) mice with combined amyloid and tau pathology and GSK-3b×Tau-P301L (biGT) mice with tauopathy only.  The results revealed that aggravation of tauopathy with highly fibrillar tangles in the hippocampus and cortex was noticed in both line of mice. Moreover, the authors also observed: (1) increased mice survival was related to alleviation of brainstem tauopathy; (2) considerable cognitive deficits were observed in biAT and biGT mice; (3) both GSK-3 isozymes were activated in the brain of parental APP-V717I amyloid mice. Taken together, these results suggest that amyloid induces tauopathy through activation of GSK-3b.

 

 

References:

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Thomas P and Fenech M: Areview of genome mutation and Alzheimer’s disease. Mutagenesis 2007, 22: 15-33,