Fractalkine signaling and Tau hyper-phosphorylation are associated with autophagic alterations in lentiviral Tau and Aβ1-42 gene transfer models.

Tau hyper-phosphorylation (p-Tau) and neuro-inflammation are hallmarks of neurodegeneration. Previous findings suggest that microglial activation via CX3CL1 promotes p-Tau. We examined inflammation and autophagic p-Tau clearance in lentiviral Tau and mutant P301L expressing rats and used lentiviral Aβ1-42 to induce p-Tau. Lentiviral Tau or P301L expression significantly increased caspase-3 activity and TNF-α, but CX3CL1 was significantly higher in animals expressing Tau compared to P301L. Lentiviral Aβ1-42 induced p-Tau 4 weeks post-injection, and increased caspase-3 activation (8-fold) and TNF-α levels. Increased levels of ADAM-10/17 were also detected with p-Tau. IL-6 levels were increased but CX3CL1 did not change in the absence of p-Tau (2 weeks); however, p-Tau reversed these effects, which were associated with increased microglial activity. We observed changes in autophagic markers, including accumulation of autophagic vacuoles (AVs) and p-Tau accumulation in autophagosomes but not lysosomes, suggesting alteration of autophagy. Taken together, microglial activation may promote p-Tau independent of total Tau levels via CX3CL1 signaling, which seems to depend on interaction with inflammatory markers, mainly IL-6. The simultaneous change in autophagy and CX3CL1 signaling suggests communication between microglia and neurons, raising the possibility that accumulation of intraneuronal amyloid, due to lack of autophagic clearance, may lead microglia activation to promote p-Tau as a tag for phagocytic degradation.