Figure 6.

Experience diminishes Aβ oligomers formation and phospho-tau through GSK-3β. Additional characterization of Aβ pathology in the experienced (denoted as E) 12 month 3xTg-AD mice against the naive (denoted as N) animals revealed a decrease in Aβ oligomers levels, as shown by A11 dot blot (A, quantified inE;p = 0.051). Analysis of 6E10 blots revealed differences in a band picked up at 56 kDa, which has been linked previously to cognitive decline, which significantly decreased in the experienced animals (B). In support of this band being, at least in part, made up of Aβ oligomers (12-mers), 10% HFIP treatment, which is known to break up oligomers, was found to decrease this band (C). To explore further why Aβ pathology was not relocalized in the experienced animals, as in the naive, putative Aβ transporter steady-state levels were investigated (D), and significant reduction was seen in LRP light chain but no differences in ApoE or TGF1β, as quantified and normalized to β-actin levels (E). Given the apparent retardation of Aβ pathology in the experienced group and the sequential relationship between Aβ and tau pathology, phosphorylated tau steady-state levels were studied. Whereas steady-state levels of total tau were unaltered, phosphorylation at AT8, AT180, and AT270 sites were significantly reduced in the experienced animals (F) as quantified and normalized to β-actin (G). Steady-state levels of GSK3β or Cdk5 were unaffected, as were levels of p25 and p35, which can underlie tau phosphorylation (H). However, phosphorylated GSK3β at Ser9, an inhibitory phosphorylation site, was significantly increased in the experienced group, indicating decreased GSK3β activity as quantified and normalized to β-actin (I). *p < 0.05 with respect to naive mice.