The relationship between the pathogenic amyloid beta-peptide species Abeta1-42 and tau pathology has been well studied and suggests that Abeta1-42 can accelerate tau pathology in vitro and in vivo. The manners if any in which Abeta1-40 interacts with tau remains poorly understood.
In order to answer this question, we used cell-based system, transgenic fly and transgenic mice as models to study the interaction between Abeta1-42 and Abeta1-40.
Results:
In our established cellular model, live cell imaging (using confocal microscopy) combined with biochemical data showed that exposure to Abeta1-42 induced cleavage, phosphorylation and aggregation of wild-type/full length tau while exposure to Abeta1-40 didn’t. Functional studies with Abeta1-40 were carried out in tau-GFP transgenic flies and showed that Abeta1-42, as previously reported, disrupted cytoskeletal structure while Abeta1-40 had no effect at same dose.
To further explore how Abeta1-40 affects tau pathology in vivo, P301S mice (tau transgenic mice) were injected intracerebrally with either Abeta1-42 or Abeta1-40. We found that treatment with Abeta1-42 induced tau phosphorylation, cleavage and aggregation of tau in P301S mice.
By contrast, Abeta1-40 injection didn’t alter total tau, phospho-tau (recognized by PHF-1) or cleavage of tau, but interestingly, phosphorylation at Ser262 was shown to be significantly decreased after direct inject of Abeta1-40 into the entorhinal cortex of P301S mice.
Conclusions:
These results demonstrate that Abeta1-40 plays different role in tau pathogenesis compared to Abeta1-42. Abeta1-40 may have a protective role in tau pathogenesis by reducing phosphorylation at Ser262, which has been shown to be neurotoxic.
Author: Xiaoyan HuXiaoling LiMingrui ZhaoAndrew GottesdienerWenjie LuoSteven Paul
Credits/Source: Molecular Neurodegeneration 2014, 9:52
Published on: 2014-11-23
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