3.4 Overexpression of Lf in astrocytes enhances PP2A activity and reduces tau phosphorylation in APP/PS1 mouse brains
APP phosphorylation is modulated by several enzymes such as CDK5, GSK3α/β and PP2A (Keeney et al., 2012; Lee et al., 2003; Shentu et al., 2018). Our results revealed that the level of p-CDK5 was reduced, and p-GSK3α/β (Ser21/9) was upregulated, while p-ERK1/2 was unaltered, in the APP/PS1/Lf mice compared to that in APP/PS1 mice (Fig. 4A). Interestingly, the p-p38 expression was considerably upregulated in APP/PS1/Lf mice, which was accompanied with the increased activity of PP2A in the APP/PS1/Lf mice compared to that in APP/PS1 mice despite the expressions of PP2Ac (the catalytic subunit of PP2A) remained similar in the different gene type mouse brains (Fig. 4B-C). These data suggested that overexpression of Lf in astrocytes may inhibit APP phosphorylation via suppressing CDK5 and GSK3α/β activities and increasing PP2A activity in APP/PS1 mouse brains.
Notably, tau phosphorylation is regulated by the activities of CDK5, GSK3α/β and PP2A (Keeney et al., 2012). The phosphorylations of tau at Thr181 and Ser404 were significantly increased in Astro-Lf mice compared to WT mice, and the phosphorylations of tau at Thr181, Ser396 and Ser404 were significantly reduced in the APP/PS1/Lf mice compared to those in APP/PS1 mice (Fig. 4D-E), suggesting that overexpression of Lf in astrocytes also effectively inhibited the tau phosphorylation in APP/PS1 mouse brains.