Renzhi Wang

Cell adhesion molecule pathway genes are regulated by cis-regulatory SNPs and show significantly altered expression in Alzheimer's disease brains.

We previously identified the cell adhesion molecule (CAM) pathway as a consistent signal in 2 Alzheimers disease (AD) genome-wide association studies (GWAS). However, the genetic mechanisms of the CAM pathway in AD are unclear. Here, we conducted pathway analysis using (1) Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathways; (2) 4 brain expression GWAS datasets; and (3) 2 whole-genome AD case-control expression datasets. Using the 4 brain expression GWAS datasets, we identified that genes regulated by cis-regulatory single-nucleotide polymorphisms (SNPs) were significantly enriched in the CAM pathway (p = 2.05E-06, p = 6.10E-07, p = 2.05E-06, and p = 1.47E-07 for each dataset). Interestingly, CAM is a significantly enriched pathway using down-regulated genes (raw p = 0.0235 and adjusted p = 0.0305) and all differentially expressed genes (raw p = 0.0105 and adjusted p = 0.0156) in dataset 5, and all differentially expressed genes (raw p = 0.0041 and adjusted p = 0.0062) in dataset 6. Collectively, our results show that CAM pathway genes are regulated by cis-regulatory SNPs and show significantly altered expression in AD. We believe that our results advance the understanding of AD mechanisms and will be useful for future genetic studies of AD.

Intra-ventricular infusion of rAAV1-EGFP resulted in transduction in multiple regions of adult rat brain: a comparative study with rAAV2 and rAAV5 vectors.

Most gene transfer studies conducted in the central nervous system (CNS) with recombinant adeno-associated virus (rAAV) vectors have been carried out by direct intra-parenchymal injection. However, this delivery method usually results in transduction of cells in only a limited region and is quite invasive, which may hamper its potential clinical application. Injection of viral vectors into the cerebrospinal fluid (CSF) may provide an alternative strategy for widespread gene delivery to the CNS via the subarachnoid space. In this study we compared the transduction abilities of rAAV types 1, 2, and 5 when infused directly into the right lateral cerebral ventricle of adult rats. Multiple structures in the vicinity of the lateral ventricle were transduced by rAAV1, but not by rAAV2 or rAAV5 vectors. Double immunolabeling showed that the transduced cells included not only neurons, but also glia. Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) experiments demonstrated that rAAV1-mediated EGFP mRNA expression was significantly higher than that induced by either rAAV2 or 5. Our data suggest that intra-ventricular infusion of rAAV1 vectors provides a useful method for broad gene delivery to cells in the adult rat CNS.

Expression quantitative trait loci regulate HNF4A and PTBP1 expression in human brains

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the elderly. Santiago and Potashkin (1) recently performed a network-based metaanalysis of four independent microarray datasets and identified hepatocyte nuclear factor 4 alpha (HNF4A) and polypyrimidine tract binding protein 1 (PTBP1) to be the longitudinally dynamic biomarkers for PD. They found that HNF4A is a central regulatory hub gene up-regulated in blood of PD patients and PTBP1 is the most down-regulated gene (1).

Identifying the Association Between Alzheimer’s Disease and Parkinson’s Disease Using Genome-Wide Association Studies and Protein-Protein Interaction Network

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the first and second most common neurodegenerative diseases in the elderly. Shared clinical and pathological features have been reported. Recent large-scale genome-wide association studies (GWAS) have been conducted and reported a number of AD and PD variants. Until now, the underlying genetic mechanisms for all these newly identified PD variants as well as the association between AD and PD are still unclear exactly. We think that PD variants may contribute to AD and PD by influence on brain gene expression. Here, we conducted a systems analysis using (1) AD and PD variants (Pu2009<u20095.00E−08) identified by the published GWAS; (2) four brain expression GWAS datasets using expression quantitative trait loci from the cerebellum and temporal cortex; (3) large-scale AD GWAS from the Alzheimer Disease Genetics Consortium (ADGC); (4) a protein-protein interaction network. Our results indicated that PD variants around the 17q21 were associated with gene expression and suggestive AD risk. We also identified significant interaction among AD and PD susceptibility genes. We believe that our findings may explain the underlying genetic mechanisms for newly identified PD variants in PD and AD, as well as the association between AD and PD, which may be very useful for future genetic studies for both diseases.

Potential of neural stem cell-based therapies for Alzheimer's disease

Alzheimers disease (AD), known to be a leading cause of dementia that causes heavy social and financial burdens worldwide, is characterized by progressive loss of neurons and synaptic connectivity after depositions of amyloid‐β (Aβ) protein. Current therapies for AD patients can only alleviate symptoms but cannot deter the neural degeneration, thus providing no long‐term recovery. Neural stem cells (NSCs), capable of self‐renewal and of differentiation into functional neurons and glia, have been shown to repair damaged networks and reverse memory and learning deficits in animal studies, providing new hope for curing AD patients by cell transplantation. Under AD pathology, the microenvironment also undergoes great alterations that affect the propagation of NSCs and subsequent therapeutic efficiency, calling for measures to improve the hostile environment for cell transplantation. This article reviews the therapeutic potential of both endogenous and exogenous NSCs in the treatment of AD and the challenges to application of stem cells in AD treatment, particularly those from the microenvironmental alterations, in the hope of providing more information for future research in exploiting stem cell‐based therapies for AD.

Intrastriatal Transplantation of Human Neural Stem Cells Restores the Impaired Subventricular Zone in Parkinsonian Mice

Cell replacement therapy using neural stem cells (NSCs) transplantation has recently emerged as a promising method of Parkinsons disease (PD) treatment; however, the underlying mechanisms are not fully understood. To gain new insights into the mechanisms of 6‐hydroxydopamine (6‐OHDA)‐induced lesioning and therapeutic efficacy of human NSCs (hNSCs) transplantation, the striatum (ST) of intrastriatal 6‐OHDA‐injected parkinsonian mice were unilaterally engrafted with undifferentiated hNSCs. A high‐throughput quantitative proteomic approach was used to characterize the proteome profiles of PD‐related brain regions such as the SN, ST, olfactory bulb, and subventricular zone (SVZ) in these mice. The abundance of more than 5,000 proteins in each region was determined with high confidence in this study, which is the most extensive proteomic study of PD mouse models to date. In addition to disruption of the DA system, the quantitative analysis demonstrated profound disturbance of the SVZ proteome after 6‐OHDA insult. After hNSC engraftment, the SVZ proteome was restored and the astrocytes in the ST were greatly activated, accompanied by an increase in neurotrophic factors. Furthermore, bioinformatics analysis demonstrated that the changes in the proteome were not caused by the proliferation of hNSCs or their progeny, but rather by the reaction of endogenous stem cells. Overall, this study elucidates the unexpected role of SVZ cells in PD progress and treatment, thereby providing new therapeutic targets for PD. Stem Cells 2017;35:1519–1531

Temporal lobe in human aging: A quantitative protein profiling study of samples from Chinese Human Brain Bank.

The temporal lobe is a portion of the cerebral cortex with critical functionality. The age-related protein profile changes in the human temporal lobe have not been previously studied. This 4-plex tandem mass tag labeled proteomic study was performed on samples of temporal lobe from Chinese donors. Tissue samples were assigned to four age groups: Group A (the young, age: 34±13 years); Group B (the elderly, 62±5 years); Group C (the aged, 84±4 years) and Group D (the old, 95±1 years). Pooled samples from the different groups were subjected to proteomics and bioinformatics analysis to identify age-related changes in protein expression and associated pathways. We isolated 5072 proteins, and found that 67 proteins were downregulated and 109 proteins were upregulated in one or more groups during the aging process. Western blotting assays were performed to verify the proteomic results. Bioinformatic analysis identified proteins involved in neuronal degeneration, including proteins involved in neuronal firing, myelin sheath damage, and cell structure stability. We also observed the accumulation of extracellular matrix and lysosomal proteins which imply the occurrence of fibrosis and autophagy. Our results suggest a series of changes across a wide range of proteins in the human temporal lobe that may relate to aging and age-related neurodegenerative disorders.

Biocompatibility and magnetic resonance imaging characteristics of carbon nanotube yarn neural electrodes in a rat model

BackgroundImplantation of deep brain stimulation (DBS) electrodes is a landmark therapy for movement disorders and some mental conditions. Compared to conventional platinum–iridium (Pt–Ir) electrodes, carbon nanotube yarns (CNTY) electrodes have improved stability and interface characteristics with less distortion during high field strength MRI. Sprague–Dawley rat models were used to examine thein vivo histological and imaging properties of biocompatible CNTY throughout the subacute period.MethodsSprague–Dawley rats received CNTY (nxa0=xa016) or Pt–Ir control (nxa0=xa016) electrodes. Behavioral markers, body weight, and survival were recorded. Comparative histology (HE, NeuN, CD68, and GFAP) was performed at 1, 6, and 12xa0weeks post-implantation; 3.0T MRI was performed at 1 and 12xa0weeks.ResultsOf 32 rats, 30 (15 per group) survived implantation without reduced activity, paralysis, or incapacity to feed. Following implantation, progressive decreases in macrophage activation and neuron-depleted margins surrounding electrodes were observed in both groups. Inflammatory marker expression (CD68) was significantly lower in rats with implanted CNTY electrodes compared to controls at all time points. CNTY electrodes also caused less inflammation and shallower depths of macrophage penetration and neural disruption relative to the interface. Artifacts and distortion were observed on MRI of Pt–Ir but not CNTY electrodes.ConclusionsCNTY electrodes exhibited reduced inflammatory margins compared to Pt–Ir electrodes throughout the subacute period, indicating reduced initial trauma, better overall biocompatibility, and reduced fibrous tissue formation. Coupled with less MRI distortion, CNTY electrodes may be useful alternatives when there is a need to monitor electrode placement by MRI.

Protein profile changes in the frontotemporal lobes in human severe traumatic brain injury.

Severe traumatic brain injury (sTBI) is a serious public health issue with high morbidity and mortality rates. Previous proteomic studies on sTBI have mainly focused on human cerebrospinal fluid and serum, as well as on brain protein changes in murine models. However, human proteomic data in sTBI brain is still scarce. We used proteomic and bioinformatic strategies to investigate variations in protein expression levels in human brains after sTBI, using samples from the Department of Neurosurgery, Affiliated Hospital of Hebei University (Hebei, China). Our proteomic data identified 4031 proteins, of which 160 proteins were overexpressed and 5 proteins were downregulated. Bioinformatics analysis showed significant changes in biological pathways including glial cell differentiation, complement activation and apolipoprotein catalysis in the statin pathway. Western blot verification of protein changes in a subset of the available tissue samples showed results that were consistent with the proteomic data. This study is one of the first to investigate the whole proteome of human sTBI brains, and provide a characteristic signature and overall landscape of the sTBI brain proteome.

Primary pituitary fibrosarcoma presenting with multiple metastases: A case report and literature review

Even though many cases of pituitary fibrosarcoma (PF) have been reported, the etiologic classification of these tumors, however, remains undefined. Moreover, owing to the paucity of available case studies, the clinical characteristics of primary pituitary fibrosarcoma (PPF) have not been fully described. We report a 26-year-old female with pathologically confirmed PPF, who presented with features of elevated intracranial pressure, oculomotor nerve palsy, field defects and panhypopituitarism. Despite the combination therapy, which included tumor removal, radiotherapy, and chemotherapy, magnetic resonance imaging demonstrated multiple intracranial and extracranial metastases at a seven-month follow-up, and the survival duration from diagnosis was only 11 months. Based on a review of the literature, we propose preliminary etiologic classification criteria for PF as well as a new therapeutic approach to reduce PPF recurrence and metastasis, including extended surgical resection and postoperative whole-brain radiotherapy.