Xue Yao

p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer's disease.

In Alzheimer’s disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer’s patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.

Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer's disease.

Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimers disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy.

Differential levels of p75NTR ectodomain in CSF and blood in patients with Alzheimer's disease: a novel diagnostic marker

Alzheimer’s disease (AD) is the primary cause of dementia in the elderly. The ectodomain of p75 neurotrophin receptor (p75NTR-ECD) has been suggested to play important roles in regulating beta-amyloid (Aβ) deposition and in protecting neurons from the toxicity of soluble Aβ. However, whether and how the serum and cerebrospinal fluid (CSF) levels of p75NTR-ECD change in patients with AD are not well documented. In the present study, we determined the concentrations of serum p75NTR-ECD in an AD group, a Parkinson disease group and a stroke group, as well as in a group of elderly controls without neurological disorders (EC). We also determined the levels of CSF p75NTR-ECD in a subset of the AD and EC groups. Our data showed that a distinct p75NTR-ECD profile characterized by a decreased CSF level and an increased serum level was present concomitantly with AD patients but not with other diseases. p75NTR-ECD levels in both the serum and CSF were strongly correlated with Mini-Mental State Examination (MMSE) scores and showed sound differential diagnostic value for AD. Moreover, when combining CSF Aβ42, CSF Aβ42/40, CSF ptau181 or CSF ptau181/Aβ42 with CSF p75NTR-ECD, the area under the receiver operating characteristic curve (AUC) and diagnostic accuracies improved. These findings indicate that p75NTR-ECD can serve as a specific biomarker for AD and the determination of serum and CSF p75NTR-ECD levels is likely to be helpful in monitoring AD progression.

Gene Expression Analysis at Multiple Time Points Identifies Key Genes for Nerve Regeneration

Introduction: The purpose of this study was to provide a comprehensive understanding of gene expression during Wallerian degeneration and axon regeneration after peripheral nerve injury. Methods: A microarray was used to detect gene expression in the distal nerve 0, 3, 7, and 14 days after sciatic nerve crush. Bioinformatic analysis was used to predict function of the differentially expressed mRNAs. Microarray results and the key pathways were validated by quantitative real‐time polymerase chain reaction (qRT‐PCR). Results: Differentially expressed mRNAs at different time‐points (3, 7, and 14 days) after injury were identified and compared with a control group (0 day). Nine general trends of changes in gene expression were identified. Key signal pathways and 9 biological processes closely associated with nerve regeneration were identified and verified. Conclusions: Differentially expressed genes and biological processes and pathways associated with axonal regeneration may elucidate the molecular‐biological mechanisms underlying peripheral nerve regeneration. Muscle Nerve 55: 373–383, 2017

Time-dependent differential expression of long non-coding RNAs following peripheral nerve injury

Long non-coding RNAs (lncRNAs) are widely accepted as key players in various biological processes. However, the roles of lncRNA in peripheral nerve regeneration remain completely unknown. Thus, in this study, we performed microarray analysis to measure lncRNA expression in the distal segment of the sciatic nerve at 0, 3, 7 and 14 days following injury. We identified 5,354 lncRNAs that were differentially expressed: 3,788 lncRNAs were differentially expressed between days 0 and 3; 3,314 lncRNAs were differentially expressed between days 0 and 7; and 2,400 lncRNAs were differentially expressed between days 0 and 14. The results of RT-qPCR of two dysregulated lncRNAs were consistent with those of microarray analysis. Bioinformatics approaches, including lncRNA classification, gene ontology (GO) analysis and target prediction, were utilized to investigate the functions of these dysregulated lncRNAs in peripheral nerve damage. Importantly, we predicted that several lncRNA-mRNA pairs may participate in biological processes related to peripheral nerve injury. RT-qPCR was performed for the preliminary verification of three lncRNA-mRNA pairs. The overexpression of NONMMUG014387 promoted the proliferation of mouse Schwann cells. Thus, the findings of our study may enhance our knowledge of the role of lncRNAs in nerve injury.

The Effectiveness of Transforaminal Versus Caudal Routes for Epidural Steroid Injections in Managing Lumbosacral Radicular Pain: A Systematic Review and Meta-Analysis.

AbstractEpidural steroid injection (ESI) is one of the most commonly used treatments for radiculopathy. Previous studies have described the effectiveness of ESI in the management of radiculopathy. However, controversy exists regarding the route that is most beneficial and effective with respect to the administration of epidural steroids, as both transforaminal (TF) and caudal (C) routes are commonly used.This analysis reviewed studies comparing the effectiveness of TF-ESIs with that of C-ESIs in the treatment of radiculopathy as a means of providing pain relief and improving functionality. This meta-analysis was performed to guide clinical decision-making.The study was a systematic review of comparative studies.A systematic literature search was performed using the PubMed, EMBASE, and Cochrane Library databases for trials written in English. The randomized trials and observational studies that met our inclusion criteria were subsequently included. Two reviewers, respectively, extracted data and estimated the risk of bias. All statistical analyses were performed using Review Manager 5.3.Six prospective and 2 retrospective studies involving 664 patients were included. Statistical analysis was performed utilizing only the 6 prospective studies. Although slight pain and functional improvements were noted in the TF-ESI groups compared with the C-ESI groups, these improvements were neither clinically nor statistically significant.The limitations of this meta-analysis resulted primarily from the weaknesses of the comparative studies and the relative paucity of patients included in each study.Both the TF and C approaches are effective in reducing pain and improving functional scores, and they demonstrated similar efficacies in the management of lumbosacral radicular pain.

Mechanisms underlying the promotion of functional recovery by deferoxamine after spinal cord injury in rats

Deferoxamine, a clinically safe drug used for treating iron overload, also repairs spinal cord injury although the mechanism for this action remains unknown. Here, we determined whether deferoxamine was therapeutic in a rat model of spinal cord injury and explored potential mechanisms for this effect. Spinal cord injury was induced by impacting the spinal cord at the thoracic T10 vertebra level. One group of injured rats received deferoxamine, a second injured group received saline, and a third group was sham operated. Both 2 days and 2 weeks after spinal cord injury, total iron ion levels and protein expression levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β and the pro-apoptotic protein caspase-3 in the spinal cords of the injured deferoxamine-treated rats were significantly lower than those in the injured saline-treated group. The percentage of the area positive for glial fibrillary acidic protein immunoreactivity and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were also significantly decreased both 2 days and 2 weeks post injury, while the number of NeuN-positive cells and the percentage of the area positive for the oligodendrocyte marker CNPase were increased in the injured deferoxamine-treated rats. At 14–56 days post injury, hind limb motor function in the deferoxamine-treated rats was superior to that in the saline-treated rats. These results suggest that deferoxamine decreases total iron ion, tumor necrosis factor-α, interleukin-1β, and caspase-3 expression levels after spinal cord injury and inhibits apoptosis and glial scar formation to promote motor function recovery.

MicroRNA-29a regulates neural stem cell neuronal differentiation by targeting PTEN.

Neural stem cells (NSCs) are self‐renewing, pluripotent, and undifferentiated cells which have benefits as candidates for central nervous system (CNS) injury. However, the transplanted NSCs usually maintain their undifferentiated characteristics, or differentiated potentially along the glial lineage after transplantation. MicroRNAs (miRNAs) are small, non‐coding RNAs that play key roles in cell differentiation. However, it is unknown whether miR‐29a could play a role in the process of NSCs differentiation. Primary NSCs were derived from rat embryonic cortex. Lentiviral vector‐mediated miR‐29a (LV‐miR‐29a) and negative control (LV‐null) were infected into NSCs. Quantitative real‐time PCR was used to detect expression of miR‐29a and PTEN. Immunocytochemistry was used to stain neurons, astrocytes, and oligodendrocytes. Dual luciferase assay to study the interaction between miR‐29a and PTEN. The current study showed that the expression of miR‐29a was upregulated during NSC differentiation, while the expression of PTEN was downregulated during NSC differentiation. After infection with LV‐miR‐29a, MAP‐2‐positive neurons significantly increased, and GFAP‐positive astrocytes significantly decreased. Furthermore, we demonstrated that PTEN is a molecular target of miR‐29a. miR‐29a promote the neuronal differentiation and decrease the astrocytes differentiation of NSCs via targeting PTEN. This may give insight into a novel mechanism of NSC differentiation and provide a promising therapeutic target.

Aquatic Exercises in the Treatment of Low Back Pain: A Systematic Review of the Literature and Meta-analysis of Eight Studies

Objective Low back pain is the most common musculoskeletal condition with a high prevalence. There was no sufficient evidence to recommend that aquatic exercise was potentially beneficial to patients with low back pain. The aim of this study was to systematically analyze all evidence available in the literature about effectiveness of the aquatic exercise. Design A comprehensive search of PubMed, the Cochrane Library, Embase, and Cumulative Index to Nursing and Allied Health was conducted from their inceptions to November 2016 for randomized controlled trials, which concerned the therapeutic aquatic exercise for low back pain. The results were expressed in terms of standardized mean difference and the corresponding 95% confidence interval. Results Eight trials involving 331 patients were included in the meta-analysis, and the results showed a relief of pain (standardized mean difference = −0.65, 95% confidence interval = −1.16 to −0.14) and physical function (standardized mean difference = 0.63, 95% confidence interval = 0.17 to 1.09) after aquatic exercise. However, there was no significant effectiveness with regard to general mental health in aquatic group (standardized mean difference = 0.46; 95% confidence interval = −0.22 to 1.15). Conclusions Aquatic exercise can statistically significantly reduce pain and increase physical function in patients with low back pain. Further high-quality investigations on a larger scale are required to confirm the results.

Epidemiological profile of thoracolumbar fracture (TLF) over a period of 10 years in Tianjin, China

Context/Objective: The objective of the research was to illustrate the epidemiology profile of thoracolumbar fracture (TLF) in Tianjin Medical University General Hospital, China, from 2006–2015. Design: Hospital-based retrospective study. Setting: Tianjin Medical University General Hospital. Methods: Medical records of inpatient patients with TLF from 1 January 2006 to December 2015 were collected. Detailed information on epidemiological characters were analyzed based on the medical records suffering from TLF from T11-L2 level, including incidence, age and sex, marital, occupation, etiology and fracture type, types of injuries. Results: Totally 132 cases were identified. The incidence rate was 2.4 patient per million population at 2015. Male-to-female ratio was 1.4:1, with a mean age of 49.1 ± 17.7 years. The cases number in 46–60 group, totally 35 and accounting for 26.5%, was the largest. There is a significant differences of cases number between 2011–2015 group and 2006–2010 group. Retiree, taken up 48.5%, was the largest group among TLF patients. The most common injury level was T12 (34) accounting for 25.7%. Falls (57, 43.2%) (low falls and high falls) were the leading causes, followed by motor vehicle collisions (MVCs) (23, 17.4%).Compression is the only type of osteoporosis and took up 55.3%. Conclusions: The incidence ratio is increased annually in TMUGH. Male was more vulnerable than female based on different social character. The average age was older in 2011–2015, retiree accounted for the main proportion and compression took up the largest percentage, the mean age increased and osteoporosis takes more in recent years.