Figure 8.

Prnp gene ablation attenuates Aβ-induced activation of Fyn and tau hyperphosphorylation in vivo. Gene ablation of Prnp modulates Fyn activation and tau phosphorylation at pY18 in brains of aged transgenic APPPS1⁺×Prnp animals. A, Protein levels of low-molecular-weight Aβ oligomers, total Fyn, and pY416-Src were assessed by quantitative Western blot (WB). 6E10 was used for Aβ. A marked reduction of pY416 was revealed in APPPS1⁺×Prnp^−/− compared with APPPS1⁺×Prnp^+/− mice. B, Relative protein levels for total Fyn and pY416-Fyn determined by densitometry analyses. C, D, Prnp gene deletion limits tau hyperphorphorylation and missorting in vivo. PY18-tau and total tau levels were measured by WB using either intracellular-enriched or membrane-enriched protein extracts (C) and quantified by software analysis (D). APPPS1⁺×Prnp^−/− mice showed a more than twofold reduction in tau phosphorylation at Y18 compared with APPPS1⁺×Prnp^+/− littermates (bars represent the mean ± SD; *p < 0.05, ANOVA followed by Student's t test; n ≥ 3 animals/genotype/age/experiment).