title: 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.
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Ioannis
authors: I
authors: Sotiropoulos
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: André T
authors: AT
authors: Lopes
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Vitor
authors: V
authors: Pinto
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Sofia
authors: S
authors: Lopes
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Sara
authors: S
authors: Carlos
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Sara
authors: S
authors: Duarte-Silva
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Andreia
authors: A
authors: Neves-Carvalho
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Filipa
authors: F
authors: Pinto-Ribeiro
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Sara
authors: S
authors: Pinheiro
authors: TEM unit, IBMC, Porto, Portugal.
authors: Rui
authors: R
authors: Fernandes
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Armando
authors: A
authors: Almeida
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. Electronic address: njcsousa@ecsaude.uminho.pt.
authors: Nuno
authors: N
authors: Sousa
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. Electronic address: hugoalmeida@ecsaude.uminho.pt.
authors: Hugo
authors: H
authors: Leite-Almeida
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D007839:Functional Laterality; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000378:metabolism; D036421:Nerve Fibers, Unmyelinated / Q000473:pathology* / Q000648:ultrastructure; D010146:Pain / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D010812:Physical Stimulation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D013997:Time Factors; D016875:tau Proteins / Q000172:deficiency*
chemical_list: D004676:Myelin Basic Protein; D016760:Proto-Oncogene Proteins c-fos; D016875:tau Proteins
keywords: C-fibers; Myelination; Pain; Peripheral nerve; Tau