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

Abstract

SummaryDementia 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 (4–6 months) 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.

Tau protein is essential for stress-induced brain pathology

“…This observation is in line with other approaches using Tau-lowering strategies to tackle neuropathologies with diverse etiology (1,3,24). Interestingly, in line with previous reports (14,16,43 but also see ref. 44), the absence of Tau does not impact on the behavioral, neurostructural, or endocrine profile of adult animals under normal conditions, does not interfere with the endocrine response to stress, and thus does not pose a threat to the organism's survival.…”

Endolysosomal degradation of Tau and its role in glucocorticoid‐driven hippocampal malfunction

“…Previous studies showed that exposure to stress or high GC levels induced Tau accumulation, dendritic atrophy, and synapse loss in animals (Pinheiro et al , ; Lopes et al , ), and that these hippocampal deficits were Tau‐dependent (Lopes et al , ,b). To test whether Rab35 could protect against these GC‐induced effects, we injected middle‐aged rats with adeno‐associated virus (AAV) to express EGFP or EGFP‐Rab35 in excitatory neurons of the hippocampus under control of the CaMKIIα promoter (Fig C).…”

“…Furthermore, emerging studies support a crucial role for Tau in diverse brain pathologies (for review, see Sotiropoulos et al, ) including prolonged exposure to stressful conditions, a known risk factor for AD and major depressive disorder (Vyas et al , ). In particular, recent studies demonstrate that exposure to chronic environmental stress or the major stress hormones, glucocorticoids (GC), triggers the accumulation of Tau and its synaptic missorting, precipitating dendritic atrophy and synaptic dysfunction in a Tau‐dependent manner (Pinheiro et al , ; Lopes et al , ,b; Pallas‐Bazarra et al , ; Dioli et al , ). However, the cellular mechanisms responsible for stress/GC‐induced accumulation of Tau remain unclear.…”

Characterization of Brain-Penetrant Pyrimidine-Containing Molecules with Differential Microtubule-Stabilizing Activities Developed as Potential Therapeutic Agents for Alzheimers Disease and Related Tauopathies

“…It was therefore somewhat surprising that genetic knockout of murine tau was initially reported to result in no overt phenotype (Harada et al, 1994;Dawson et al, 2001). However, mounting evidence suggests that age-dependent MT and motor function deficits develop in tau-depleted mice (Dawson et al, 2010;Lopes et al, 2016). In addition, primary neurons derived from tau knockout mice show impaired neurite outgrowth (Dawson et al, 2001).…”