Selective impact of Tau loss on nociceptive primary afferents and pain sensation

Abstract

Tau protein hyperphosphorylation and consequent malfunction are hallmarks 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. Thus, we tested Tau-null (Tau-/-) and Tau+/+ mice for acute thermal pain (Hargreaves' test), acute and tonic inflammatory pain (formalin test) and mechanical allodynia (Von Frey test). We report that Tau-/- animals presented a decreased response to acute noxious stimuli when compared to Tau+/+ while their pain-related behavior is augmented under tonic painful stimuli. This increased reactivity to tonic pain was accompanied by enhanced formalin-evoked c-fos staining of second order nociceptive neurons at Tau-null dorsal horn. In addition, we analyzed the primary afferents conveying nociceptive signals, estimating sciatic nerve fiber density, myelination and nerve conduction. Ultrastructural analysis revealed a decreased C-fiber density in the sciatic nerve of Tau-null mice and a hypomyelination of myelinated fibers (Aδ-fibers) - also confirmed by western blot analysis - followed by altered conduction properties of Tau-null sciatic nerves. 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.

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

“…It is important to note that a prior report did not find a difference in depression-like behavior in Mapt −/− [23]. Another difference from prior studies is that we did not observe changes in nociception in the Mapt −/− mice [100]. However, these studies included only males and used a different mouse strain (C57BL/6), which may explain the difference in our results.…”

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

“…Expression of an inducible, truncated tau (which retains the Fyn-binding domain but lacks microtubule-binding capability) in oligodendrocytes induced demyelination and gait abnormalities in mice [160]. MAPT −/− mice also show age-dependent degeneration of myelinated fibers, reduced nerve conduction, and progressive hypomyelination [157,237], resulting in motor [157] and nociceptive [237] impairments. Tau knockdown also restricts recovery after sciatic nerve damage, with mice showing defective myelin debris clearance and severely impaired Schwann cell migration and differentiation [285].…”

Dendritic Tau in Alzheimer’s Disease

“…The current focus on targeting dendritic tau and its associated pathways is on neurodegenerative diseases, and in particular AD. However, pre-clinical studies in different disease models would suggest that efficient tau-targeted therapies could have much broader implications, including for epileptic seizures (DeVos et al, 2013;Gheyara et al, 2014;Ittner et al, 2010;Roberson et al, 2007), stroke (Bi et al, 2017;Tuo et al, 2017), traumatic brain injury (Cheng et al, 2014), pain (Sotiropoulos et al, 2014), and stress (Lopes et al, 2016). However, targeting tau would require reliable diagnosis of underlying conditions; reducing tau increased disease severity and axonal loss in an induced experimental autoimmune encephalomyelitis model (Weinger et al, 2012).…”