Abstract
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.
Highlights
Clinical presentation of Alzheimer’s disease (AD) is complex and extends well beyond the cognitive impairments that characterize this disorder (Duker et al, 2012)
Tau abnormal hyperphosphorylation and subsequent malfunction are postulated as crucial mechanisms in AD neuronal dysfunction where hyperphosphorylated and/or aggregated forms of Tau exhibit neurodegenerative action(s) that interfere with normal Tau, sequestering and reducing soluble Tau forms (Ksiezak-Reding et al, 1988; Zhukareva et al, 2003)
These lesions are mainly found at different areas of CNS such as hippocampus and cortex some studies demonstrate the presence of Tau deficits in peripheral nervous system (PNS; e.g., autonomic ganglia and sciatic nerves Bohl et al, 1997; Holzer et al, 1999)
Summary
Clinical presentation of Alzheimer’s disease (AD) is complex and extends well beyond the cognitive impairments that characterize this disorder (Duker et al, 2012). Tau abnormal hyperphosphorylation and subsequent malfunction are postulated as crucial mechanisms in AD neuronal dysfunction where hyperphosphorylated and/or aggregated (insoluble) forms of Tau exhibit neurodegenerative action(s) that interfere with normal Tau, sequestering and reducing soluble Tau forms (Ksiezak-Reding et al, 1988; Zhukareva et al, 2003). These lesions are mainly found at different areas of CNS such as hippocampus and cortex some studies demonstrate the presence of Tau deficits in peripheral nervous system (PNS; e.g., autonomic ganglia and sciatic nerves Bohl et al, 1997; Holzer et al, 1999). This study aimed to monitor the impact of chronic loss of Tau protein in PNS efferents, primary compartment of motor circuitry, and motor performance using a battery of behavioral tests analyzing motor function in both young (4– 6 months) and old (17–22 months) TauÀ/À mice combined with a systematic morphofunctional analysis of their sciatic nerve
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