Absence of Tau triggers age-dependent sciatic nerve morphofunctional deficits and motor impairment

Dementia is the cardinal feature of Alzheimer's disease (AD), yet the clinical symptoms of this disorder also include a marked loss of motor function. Tau abnormal hyperphosphorylation and malfunction are well-established key events in AD neuropathology but the impact of the loss of normal Tau function in neuronal degeneration and subsequent behavioral deficits is still debated. While Tau reduction has been increasingly suggested as therapeutic strategy against neurodegeneration, particularly in AD, there is controversial evidence about whether loss of Tau progressively impacts on motor function arguing about damage of CNS motor components. Using a variety of motor-related tests, we herein provide evidence of an age-dependent motor impairment in Tau-/- animals that is accompanied by ultrastructural and functional impairments of the efferent fibers that convey motor-related information. Specifically, we show that the sciatic nerve of old (17-22-months) Tau-/- mice displays increased degenerating myelinated fibers and diminished conduction properties, as compared to age-matched wild-type (Tau+/+) littermates and younger (4-6months) Tau-/- and Tau+/+ mice. In addition, the sciatic nerves of Tau-/- mice exhibit a progressive hypomyelination (assessed by g-ratio) specifically affecting large-diameter, motor-related axons in old animals. These findings suggest that loss of Tau protein may progressively impact on peripheral motor system.The work was supported by grants 'PTDC/SAU-NMC/113934/2009,' 'PTDC/SAU-NSC/118194/2010,' 'SFRH/BPD/97281/2013,' PTDC/SAU-NSC/118194/2010,' 'SFRH/BPD/80118/2011,' 'SFRH/BD/89714/2012' funded by FCT-Portuguese Foundation for Science and Technology and project DoIT-Desenvolvimento e Operacionalizacao da Investigacao de Translacao (No do projeto 13853), funded by Fundo Europeu de Desenvolvimento Regional (FEDER) throughout the Programa Operacional Fatores de Competitividade (POFC). In addition, this work was also co-financed by European Union FP7 project SwitchBox (NS) and the Portuguese North Regional Operational Program (ON.2 - O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER).