title: APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.
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.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhou
authors.forename: Tianwen
authors.initials: T
authors.lastname: Huang
authors.forename: Nicole
authors.initials: N
authors.lastname: Collins
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Dai
authors.forename: Naian
authors.initials: N
authors.lastname: Xiao
authors.forename: Xilin
authors.initials: X
authors.lastname: Wu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wei
authors.forename: Jason
authors.initials: J
authors.lastname: York
authors.forename: Lanyan
authors.initials: L
authors.lastname: Lin
authors.forename: Yuangui
authors.initials: Y
authors.lastname: Zhu
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: LaDu
authors.affiliation: Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China. chenxc998@163.com.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Chen
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; C558298:Mapt protein, mouse; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C495906:Cdk5 protein, mouse; D002154:Calpain