Kaimin Wu

BACKGROUND: Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. MAIN BODY: Clinically, tauopathies can present with a range of phenotypes that include cognitive/behavioral-disorders, movement disorders, language disorders and non-specific amnestic symptoms in advanced age. Pathologically, tauopathies can be classified based on the predominant tau isoforms that are present in the inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) and blood-based tau biomarkers have the potential to be used as a routine diagnostic strategy and in the evaluation of patients with tauopathies. As tauopathies are strongly linked neuropathologically and genetically to tau protein abnormalities, there is a growing interest in pursuing of tau-directed therapeutics for the disorders. Here we synthesize emerging lessons on tauopathies from clinical, pathological, genetic, and experimental studies toward a unified concept of these disorders that may accelerate the therapeutics. CONCLUSIONS: Since tauopathies are still untreatable diseases, efforts have been made to depict clinical and pathological characteristics, identify biomarkers, elucidate underlying pathogenesis to achieve early diagnosis and develop disease-modifying therapies.

Mesenchymal stem cell (MSC) transplantation has been shown to be a potential treatment for traumatic spinal cord injury (SCI). However, there are several obstacles that need to be overcome before MSCs can be considered for clinical application, such as failure of MSCs to reach the spinal cord lesion core and possible tumor formation. Recent studies have suggested that MSC treatment was beneficial due to paracrine-secreted factors. Of these, exosomes are considered to be one of the most valuable paracrine molecules. However, the effect of exosome administration on recovery from SCI is still unclear. Therefore, our study was designed to investigate the effect of systemic administration of exosomes on the loss of motor function after SCI and examine a potential mechanism of effect. Disruption of the blood spinal cord barrier (BSCB) is a crucial factor which is detrimental to motor function recovery. Pericytes are an important component of the neurovascular unit, which play a pivotal role in maintaining structural integrity of the BSCB. Our study demonstrated that through bone mesenchymal stem cell-derived exosomes (BMSCs-exos) administration, the neuronal apoptosis was reduced, the neuronal survival and regeneration was enhanced, motor function improved compared with sham group and BMSCs-exos-free conditioned media(exos-free CM).Besides, BSCB was attenuated and pericyte coverage was significantly decreased in vivo.Furthermore, we found that exosome treatment reduced pericytes migration via down-regulation of NF-kB p65 signal, with a consequent decrease in permeability of the BSCB.In summary, we identified that exosome treatment promoted migration of pericytes and further improved integrity of BSCB via targeting the NF-kB p65 signal in pericytes. Therefore, our data suggests that exosomes may serve as a promising treatment strategy for SCI.

BMSCs). Treatment with BMSC-EXOs greatly reduced neuronal cell death, improved myelin arrangement and reduced myelin loss, increased pericyte/endothelial cell coverage on the vascular wall, decreased blood-spinal cord barrier leakage, reduced caspase 1 expression, inhibited interleukin-1β release, and accelerated locomotor functional recovery in rats with spinal cord injury. In the cell culture experiment, pericytes were treated with interferon-γ and tumor necrosis factor-α. Then, Lipofectamine 3000 was used to deliver lipopolysaccharide into the cells, and the cells were co-incubated with adenosine triphosphate to simulate injury in vitro. Pre-treatment with BMSC-EXOs for 8 hours greatly reduced pericyte pyroptosis and increased pericyte survival rate. These findings suggest that BMSC-EXOs may protect pericytes by inhibiting pyroptosis and by improving blood-spinal cord barrier integrity, thereby promoting the survival of neurons and the extension of nerve fibers, and ultimately improving motor function in rats with spinal cord injury. All protocols were conducted with the approval of the Animal Ethics Committee of Zhengzhou University on March 16, 2019.