Tau pathogenesis is promoted by Aβ1-42 but not Aβ1-40

Molecular Neurodegeneration

Steven Paul³  Wenjie Luo³  Andrew Gottesdiener³  Mingrui Zhao²  Xiaoling Li¹  Xiaoyan Hu³ 

[1] Strang Laboratory of Apoptosis & Cancer Biology, Rockefeller University, 413 East 69th Street, 10th Floor, BB 1051, mailbox #240, New York, NY 10065, USA;Department of Neurological Surgery, Weill Cornell Medical College, 413 East 69th Street, 10th Floor, BB 1051, mailbox #240, New York, NY 10065, USA;Appel Alzheimer’s Disease Research Institute, Weill Cornell Medical College, 413 East 69th Street, 10th Floor, BB 1051, mailbox #240, New York, NY 10065, USA

关键词: Cleavage;    Phosphorylation;    Aggregation;    Alzheimer’s disease;    tau;    Aβ1–40;    Aβ1–42;   

Others  :  1138626
DOI  :  10.1186/1750-1326-9-52

 received in 2014-08-25, accepted in 2014-10-29,  发布年份 2014

【 摘 要 】

Background

The relationship between the pathogenic amyloid β-peptide species Aβ1–42 and tau pathology has been well studied and suggests that Aβ1–42 can accelerate tau pathology in vitro and in vivo. The manners if any in which Aβ1–40 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 Aβ1–42 and Aβ1–40.

Results

In our established cellular model, live cell imaging (using confocal microscopy) combined with biochemical data showed that exposure to Aβ1–42 induced cleavage, phosphorylation and aggregation of wild-type/full length tau while exposure to Aβ1–40 didn’t. Functional studies with Aβ1–40 were carried out in tau-GFP transgenic flies and showed that Aβ1–42, as previously reported, disrupted cytoskeletal structure while Aβ1–40 had no effect at same dose. To further explore how Aβ1–40 affects tau pathology in vivo, P301S mice (tau transgenic mice) were injected intracerebrally with either Aβ1–42 or Aβ1–40. We found that treatment with Aβ1–42 induced tau phosphorylation, cleavage and aggregation of tau in P301S mice. By contrast, Aβ1–40 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 Aβ1–40 into the entorhinal cortex of P301S mice.

Conclusions

These results demonstrate that Aβ1–40 plays different role in tau pathogenesis compared to Aβ1–42. Aβ1–40 may have a protective role in tau pathogenesis by reducing phosphorylation at Ser²⁶², which has been shown to be neurotoxic.

【 授权许可】

   
2014 Hu et al.; licensee BioMed Central Ltd.

【 图 表 】

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