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

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

Volume: 13 Issue: 9

Author(s): Meng Zhou, Tianwen Huang, Nicole Collins, Jing Zhang, Hui Shen, Xiaoman Dai, Naian Xiao, Xilin Wu, Zhen Wei, Jason York, Lanyan Lin, Yuangui Zhu, Mary Jo LaDu and Xiaochun Chen

Affiliation:

Keywords: Apolipoprotein E, amyloid beta, Alzheimer’s disease, calpain-CDK5, EFAD mice, phosphorylation, tau.

Abstract: 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.

Cite this article as:

Zhou Meng, Huang Tianwen, Collins Nicole, Zhang Jing, Shen Hui, Dai Xiaoman, Xiao Naian, Wu Xilin, Wei Zhen, York Jason, Lin Lanyan, Zhu Yuangui, LaDu Jo Mary and Chen Xiaochun, APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice, Current Alzheimer Research 2016; 13 (9) . https://dx.doi.org/10.2174/1567205013666160415154550