Phosphorylation state of tau in the hippocampus of apolipoprotein E4 and E3 knock-in mice

The apolipoprotein E (apoE) epsilon4 allele is associated with an increased risk of sporadic as well as late-onset familial Alzheimer's disease (AD). To accurately determine the isoform-specific effects of human apoE on AD-like phosphorylation of tau, hippocampi from human apoE knock-in (KI) mice were studied by quantitative immunoblotting. There was no significant difference in phosphorylation levels of tau at nine of the 13 epitopes, for six of eight tau kinases, or in protein levels of three tau phosphatases, between apoE3-KI and apoE4-KI mouse hippocampi. However, in apoE4-KI mice, phosphorylation of tau at Ser235 was increased to similar to150%, that at Ser413 to similar to140%, while that at Ser202/Thr205 and Thr205 were decreased to similar to70%, and the protein level of tau protein kinase I/glycogen synthase kinase 3beta (TPKI/GSK3beta) was increased to similar to120%, that of extracellular signal-regulated kinase 2 (ERK2) was increased to similar to130%, compared with apoE3-KI mice.