Inhibition of autophagy causes tau proteolysis by activating calpain in rat brain.

The autophagic lysosomal system contributes to the removal of cytosolic components, and abnormality of lysosomal proteases has been reported in the brain of patients with Alzheimer's disease (AD). However, the role of lysosome in tau degradation is still elusive. Here, we infused chloroquine, 3-methyladenine or rapamycin into rat hippocampus or the lateral ventricle to manipulate the autophagic activity and measured the levels of tau protein by Western blotting. We unexpectedly observed that the level of different tau species decreased upon inhibition of lysosomal proteases or macroautophagy by chloroquine or 3-methyladenine. Furthermore, induction of autophagic activity by rapamycin did not induce degradation of tau proteins. To explore the underlying mechanisms for the increased tau degradation induced by autophagic inhibition, we used MG-132, an inhibitor of proteasome and calpain. We found that simultaneous inhibition of proteasome and calpain by MG-132 prevented the chloroquine-induced tau degradation. Further studies demonstrated that the activity of calpain was elevated whereas the activity of proteasome was suppressed in response to inhibition of autophagy by 3-methyladenine or chloroquine. Our data suggest that the lysosomal autophagic system may not degrade tau in the normal adult rat brain and inhibition of autophagy may induce tau proteolysis through activating calpain.