TAU DEPLETION RESULTS IN ALTERED PAIN SENSATION AND SCIATIC NERVE STRUCTURE

Tau protein hyperphosphorylation and consequent malfunction is a hallmark of Alzheimer's disease pathology; importantly, pain perception is diminished in these patients. In physiological conditions, Tau contributes to cytoskeletal dynamics and in this way, influences a number of cellular mechanisms including axonal trafficking, myelination and synaptic plasticity, processes that are also implicated in pain perception. However, there is no in vivo evidence clarifying the role of Tau in nociception. Herein, we assessed pain-related behaviors after a challenge with acute noxious heat, formalin (acute and tonic inflammatory pain) and light mechanical (in a peripheral neuropathy) stimuli in Ta-null and wild-type mice. We report that Tau-null animals presented a decreased response to acute noxious stimuli while pain-related behavior is augmented under chronic painful stimuli. Ultrastructural analysis revealed a decreased C-fiber density in the sciatic nerve of Tau-null mice and a hypomyelination of the small myelinated fibers (A-delta fibers) followed by altered conduction properties in the sciatic nerve of Tau-null mice. To our knowledge, this is the first in vivo study that demonstrates that Tau depletion negatively affects the main systems conveying nociceptive information to the CNS, adding to our knowledge about Tau function(s) that might also be relevant for understanding peripheral neurological deficits in different Tauopathies.