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