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APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.

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posted on 16.10.2017, 00:00 authored by Zhou M, Huang T, Collins N, Zhang J, Shen H, Dai X, Xiao N, Wu X, Wei Z, York J, Lin L, Zhu Y, LaDu MJ, Chen X
APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), particularly associated with increased levels of amyloid-β (Aβ) and amyloid deposition. However, it remains unclear whether APOE4 is associated with greater tau phosphorylation and neurofibrillary tangle formation, a hallmark of AD leading to structural disruption of the neuronal cytoskeleton. The current study used 3 and 7 month old EFAD mice, which express human APOE and over-express specifically human Aβ42 via 5 familial-AD (FAD) mutations, to investigate APOE genotype-specific effects on site-specific tau phosphorylation. The results reveal that AD-like site-specific tau phosphorylation was increased in E4FAD mice, accompanied by disrupted cortical neuronal morphology, compared to E3FAD mice. Further analysis demonstrated that the levels of CDK5, its regulatory subunits (p35 and p25) and calpain (including calpain1 and calpain2), but not GSK3β, were significantly increased in E4FAD mice compared to E3FAD mice. These results suggest that the APOE4 genotype contributes to increased site-specific tau phosphorylation via activation of the calpain-CDK5 signaling pathway.

Funding

This work was supported by a grant from the National Natural Science Foundation of China (No. 81100812 ) to Dr. Tian-wen Huang and the National Natural Science Foundation of China (No. 81171216, 91232709) to Prof. Xiao-chun Chen,and the key Clinical Specialty Discipline Construction Program of Fujian and nation, P.R.C. MJL wishes to acknowledge sources of funding NIH/NIA: P01AG03012801, R21AG048498, R21 AG051233, R21 AG044682.

History

Publisher Statement

This is the author’s version of a work that was accepted for publication in Current Alzheimer Research. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Current Alzheimer Research. 2016. 13(9): 1048-1055. doi: 10.2174/1567205013666160415154550.

Publisher

Bentham Science Publishers

issn

1567-2050

Issue date

01/09/2016

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