Inhibition of sphingomyelin synthase 1 ameliorates alzheimer-like pathology in APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1.
Abstract Sphingolipids emerge as essential modulators in the etiology of Alzheimer's disease (AD) with unclear mechanisms. Elevated levels of SM synthase 1 (SMS1), which catalyzes the synthesis of SM from ceramide and phosphatidylcholine, have been observed in the brains of Alzheimer's disease (AD), where expression of β-site APP cleaving enzyme 1 (BACE1), a rate limiting enzyme in amyloid-β (Aβ) generation, are upregulated. In the present study, we show knockdown of SMS1 via andeno associated virus (serotype 8, AAV8) in the hippocampus of APP/PS1 transgenic mice, attenuates the densities of Aβ...
Source: Experimental Neurology - September 19, 2018 Category: Neurology Authors: Lu MH, Ji WL, Xu DE, Yao PP, Zhao XY, Wang ZT, Fang LP, Huang R, Lan LJ, Chen JB, Wang TH, Cheng LH, Xu RX, Liu CF, Puglielli L, Ma QH Tags: Exp Neurol Source Type: research

Post-stroke neovascularization and functional outcomes differ in diabetes depending on severity of injury and sex: Potential link to hemorrhagic transformation.
Abstract Diabetes is associated with increased risk and worsened outcome of stroke. Previous studies showed that male diabetic animals had greater hemorrhagic transformation (HT), profound loss of cerebral vasculature, and poor behavioral outcomes after ischemic stroke induced by suture or embolic middle cerebral artery occlusion (MCAO). Females are protected from stroke until reaching the menopause age, but young females with diabetes have a higher risk of stroke and women account for the majority of stroke mortality. The current study postulated that diabetes is associated with greater vascular injury and exacer...
Source: Experimental Neurology - September 19, 2018 Category: Neurology Authors: Li W, Valenzuela JP, Ward R, Abdelbary M, Dong G, Fagan SC, Ergul A Tags: Exp Neurol Source Type: research

Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance.
This study was designed to investigate the effect of metformin on hyperphosphorylated tau proteins in diabetic encephalopathy (DE) by regulating autophagy clearance. db/db mice were randomly divided into four groups, db/+ mice were used as control group. Twelve-week old male db/db mice received consecutive intraperitoneal injection of 200 mg/kg/d metformin or (and) 10 mg/kg/d chloroquine for eight weeks. Morris water maze (MWM) tests were performed to test cognitive functions before the mice were euthanized. Metformin attenuated cognitive impairment in db/db mice, reduced hyperphosphorylated tau proteins, restored the ...
Source: Experimental Neurology - September 13, 2018 Category: Neurology Authors: Chen JL, Luo C, Pu D, Zhang GQ, Zhao YX, Sun Y, Zhao KX, Liao ZY, Lv AK, Zhu SY, Jing-Zhou, Xiao Q Tags: Exp Neurol Source Type: research

Long-term social isolation inhibits autophagy activation, induces postsynaptic dysfunctions and impairs spatial memory.
Abstract Social isolation in adolescence leads to lasting deficits in hippocampal-dependent tasks. The reported effects of isolation on learning and memory in the Morris water maze and synaptic-related proteins have been inconsistent. Moreover, the autophagy level and its effect on cognition in the isolation model are also not clear. In the present study, we did an extended isolation period up to six months to establish a stable and appropriate isolation model to investigate the cognitive changes associated with it. The mTOR inhibitor rapamycin was systemically administered to mice to determine the roles of autoph...
Source: Experimental Neurology - September 13, 2018 Category: Neurology Authors: Wang B, Wu Q, Lei L, Sun H, Michael N, Zhang X, Wang Y, Zhang Y, Ge B, Xin Y, Zhao J, Li S Tags: Exp Neurol Source Type: research

High-mobility group box-1 translocation and release after hypoxic ischemic brain injury in neonatal rats.
Abstract Inflammation contributes to neonatal brain injury. Pro-inflammatory cytokines represent key inflammatory meditators in neonatal hypoxic-ischemic (HI) brain injury. The high mobility group box-1 (HMGB1) protein is a nuclear protein with pro-inflammatory cytokine properties when it is translocated from the nucleus and released extracellularly after stroke in adult rodents. We have previously shown that HMGB1 is translocated from the nucleus to cytosolic compartment after ischemic brain injury in fetal sheep. In the current study, we utilized the Rice-Vannucci model to investigate the time course of HMGB1 tr...
Source: Experimental Neurology - September 11, 2018 Category: Neurology Authors: Chen X, Zhang J, Kim B, Jaitpal S, Meng SS, Adjepong K, Imamura S, Wake H, Nishibori M, Stopa EG, Stonestreet BS Tags: Exp Neurol Source Type: research

Mesenchymal stem cells-derived IL-6 activates AMPK/mTOR signaling to inhibit the proliferation of reactive astrocytes induced by hypoxic-ischemic brain damage.
In this study, we investigated the therapeutic effects of MSCs on astrocyte proliferation in neonatal rats subjected to HIBD. A HIBD model was established in Sprague Dawley (SD) rats, and MSCs were administered by intracerebroventricular injection 5 days after HIBD. Rat primary astrocytes were cultured, subjected to oxygen glucose deprivation (OGD) injury and then immediately co-cultured with MSCs in vitro. Immunofluorescence staining, Cell Counting Kit (CCK)-8, flow cytometry, Ca2+ imaging, enzyme-linked immunosorbent assay (ELISA), western blotting, and co-immunoprecipitation (Co-IP) were performed. We found that MSCs ...
Source: Experimental Neurology - September 10, 2018 Category: Neurology Authors: He M, Shi X, Yang M, Yang T, Li T, Chen J Tags: Exp Neurol Source Type: research

Oncostatin M-induced upregulation of SDF-1 improves Bone marrow stromal cell migration in a rat middle cerebral artery occlusion stroke model.
Abstract Bone marrow-derived mesenchymal stem cells (BMSCs) exhibit potential regenerative effects on the injured brain. However, these effects are constrained by their limited ability to migrate to the injured site. Oncostatin M (OSM) has been shown to affect the proliferation and migration of mesenchymal stem cells. Therefore, in the present study, we explored whether OSM improves BMSC migration and secretion of growth factors and cytokines in a rat middle cerebral artery occlusion (MCAO) stroke model. The effect of OSM on the proliferation and apoptosis of rat BMSCs was first assessed in vitro, and the gene and...
Source: Experimental Neurology - September 10, 2018 Category: Neurology Authors: Han J, Feng Z, Xie Y, Li F, Lv B, Hua T, Zhang Z, Sun C, Su D, Ouyang Q, Cai Y, Zou Y, Tang Y, Sun H, Jiang X Tags: Exp Neurol Source Type: research

Anticonvulsant effects after grafting of rat, porcine, and human mesencephalic neural progenitor cells into the rat subthalamic nucleus.
W, Gernert M Abstract Cell transplantation based therapy is a promising strategy for treating intractable epilepsies. Inhibition of the subthalamic nucleus (STN) or substantia nigra pars reticulata (SNr) is a powerful experimental approach for remote control of different partial seizure types, when targeting the seizure focus is not amenable. Here, we tested the hypothesis that grafting of embryonic/fetal neural precursor cells (NPCs) from various species (rat, human, pig) into STN or SNr of adult rats induces anticonvulsant effects. To rationally refine this approach, we included NPCs derived from the medial gang...
Source: Experimental Neurology - September 8, 2018 Category: Neurology Authors: Backofen-Wehrhahn B, Gey L, Bröer S, Petersen B, Schiff M, Handreck A, Stanslowsky N, Ostermeyer J, Weißing M, Staege S, Wegner F, Niemann H, Löscher W, Gernert M Tags: Exp Neurol Source Type: research

ER α and/or ERβ activation ameliorates cognitive impairment, neurogenesis and apoptosis in type 2 diabetes mellitus mice.
ERα and/or ERβ activation ameliorates cognitive impairment, neurogenesis and apoptosis in type 2 diabetes mellitus mice. Exp Neurol. 2018 Sep 07;: Authors: Tang SS, Ren Y, Ren XQ, Cao JR, Hong H, Ji H, Hu QH Abstract Estrogen receptors (ERs) are thought to be associated with the onset and progression of neurodegenerative injuries and diseases, but the relationship and mechanisms underlying between ERs and cognition in type 2 diabetes remain elusive. In the current study, we investigated the effects of ERα and ERβ on the cognition, neurogenesis and apoptosis in high-fat diet and s...
Source: Experimental Neurology - September 7, 2018 Category: Neurology Authors: Tang SS, Ren Y, Ren XQ, Cao JR, Hong H, Ji H, Hu QH Tags: Exp Neurol Source Type: research

Localised non-viral delivery of nucleic acids for nerve regeneration in injured nervous systems.
Abstract Axons damaged by traumatic injuries are often unable to spontaneously regenerate in the adult central nervous system (CNS). Although the peripheral nervous system (PNS) has some regenerative capacity, its ability to regrow remains limited across large lesion gaps due to scar tissue formation. Nucleic acid therapy holds the potential of improving regeneration by enhancing the intrinsic growth ability of neurons and overcoming the inhibitory environment that prevents neurite outgrowth. Nucleic acids modulate gene expression by over-expression of neuronal growth factor or silencing growth-inhibitory molecule...
Source: Experimental Neurology - September 6, 2018 Category: Neurology Authors: Zhang N, Chin JS, Chew SY Tags: Exp Neurol Source Type: research

α-synuclein expression from a single copy transgene increases sensitivity to stress and accelerates neuronal loss in genetic models of Parkinson's disease.
α-synuclein expression from a single copy transgene increases sensitivity to stress and accelerates neuronal loss in genetic models of Parkinson's disease. Exp Neurol. 2018 Sep 05;: Authors: Cooper JF, Spielbauer KK, Senchuk MM, Nadarajan S, Colaiácovo MP, Van Raamsdonk JM Abstract Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by the formation of α-synuclein-containing protein aggregates called Lewy bodies within the brain. A crucial role for α-synuclein in the pathogenesis of PD is also suggested by the fact that point mutat...
Source: Experimental Neurology - September 5, 2018 Category: Neurology Authors: Cooper JF, Spielbauer KK, Senchuk MM, Nadarajan S, Colaiácovo MP, Van Raamsdonk JM Tags: Exp Neurol Source Type: research

Matrices, scaffolds, and carriers for protein and molecule delivery in peripheral nerve regeneration.
Abstract Local application of exogenous agents with neurotrophic properties enhances the regenerative capacity of injured neurons, especially following reconstructions of long nerve gaps and delayed nerve repairs. Recent advances in biomaterials and biomedical engineering have provided options for the sustained and controlled release of macromolecules to the peripheral nerve. Here, we review five methods for delivering macromolecules to the peripheral nerve including mini-osmotic pumps, hydrogel-based delivery systems, nerve guidance conduits, electrospun fibers, and nerve wraps. In addition to controlling the rel...
Source: Experimental Neurology - August 31, 2018 Category: Neurology Authors: Tajdaran K, Chan K, Gordon T, Borschel GH Tags: Exp Neurol Source Type: research

Transplantation of human bone marrow stem cells into symptomatic ALS mice enhanced structural and functional blood-spinal cord barrier repair.
Abstract Accumulating evidence shows alterations in the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) in ALS patients and in animal models of disease, mainly by endothelial cell (EC) damage. Repair of the altered barrier in the CNS by replacement of ECs via cell transplantation may be a new therapeutic approach for ALS. Recently, we demonstrated positive effects towards BSCB repair by intravenous administration of unmodified human bone marrow CD34+ (hBM34+) cells at different doses into symptomatic ALS mice. However, particular benefits of these transplanted cells on microvascular integrity in sym...
Source: Experimental Neurology - August 30, 2018 Category: Neurology Authors: Garbuzova-Davis S, Haller E, Navarro S, Besong TE, Boccio KJ, Hailu S, Khatib M, Sanberg PR, Appel SH, Borlongan CV Tags: Exp Neurol Source Type: research

Directed glial differentiation and transdifferentiation for neural tissue regeneration.
Abstract Glial cells which are indispensable for the central nervous system development and functioning, are proven to be vulnerable to a harmful influence of pathological cues and tissue misbalance. However, they are also highly sensitive to both in vitro and in vivo modulation of their commitment, differentiation, activity and even the fate-switch by different types of bioactive molecules. Since glial cells (comprising macroglia and microglia) are an abundant and heterogeneous population of neural cells, which are almost uniformly distributed in the brain and the spinal cord parenchyma, they all create a natural...
Source: Experimental Neurology - August 29, 2018 Category: Neurology Authors: Justyna J, Justyna G, Malgorzata ZN, Teresa Z, Leonora B, Joanna S Tags: Exp Neurol Source Type: research

Pretreatment with low-dose fimasartan ameliorates NLRP3 inflammasome-mediated neuroinflammation and brain injury after intracerebral hemorrhage.
This study aims to investigate whether pre-stroke treatment with fimasartan, an angiotensin II receptor blocker, has anti-inflammatory effects on ICH by inhibiting the activation of the NLRP3 inflammasome. Sprague-Dawley rats were divided into five groups: sham, vehicle, low-dose (0.5 mg/kg) and regular-doses (1.0 and 3.0 mg/kg) fimasartan. These rats were treated for 30 days before the induction of collagenase-induced ICH and continuously 3 days after surgery. The mean blood pressure (BP) in the low-dose fimasartan group was not significantly different from that of control, and BP in the regular-dose groups was de...
Source: Experimental Neurology - August 29, 2018 Category: Neurology Authors: Yang X, Sun J, Kim TJ, Kim YJ, Ko SB, Kim CK, Jia X, Yoon BW Tags: Exp Neurol Source Type: research

Commentary on Giralt et al.: PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease.
Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the most common cause of dementia and the 6th leading cause of death. Although research has revealed significant information about AD, much is yet to be discovered about the precise biological changes that cause AD and how the disease could be prevented, slowed, or stopped. Accumulating evidence suggests the involvement of the non-receptor proline-rich tyrosine kinase 2 (Pyk2) in AD, but the downstream signaling events triggered by this protein and their implications on the pathology of the disease were unclear until recently. A ...
Source: Experimental Neurology - August 29, 2018 Category: Neurology Authors: Polis B, Gil-Henn H Tags: Exp Neurol Source Type: research

Genetic screening of the genes interacting with Drosophila FIG4 identified a novel link between CMT-causing gene and long noncoding RNAs.
In this study, we carried out modifier screening of the dFIG4 knockdown-induced rough eye phenotype using a set of chromosomal deficiency lines on the second chromosome. By genetic screening, we detected 9 and 15 chromosomal regions whose deletions either suppressed or enhanced the rough eye phenotype induced by the dFIG4 knockdown. By further genetic screening with mutants of individual genes in one of these chromosomal regions, we identified the gene CR18854 that suppressed the rough eye phenotype and the loss-of-cone cell phenotype. The CR18854 gene encodes a long non-coding RNA (lncRNA) consisting of 2566 bases. Mutati...
Source: Experimental Neurology - August 27, 2018 Category: Neurology Authors: Muraoka Y, Nakamura A, Tanaka R, Suda K, Azuma Y, Kushimura Y, Piccolo LL, Yoshida H, Mizuta I, Tokuda T, Mizuno T, Nakagawa M, Yamaguchi M Tags: Exp Neurol Source Type: research

Dephosphorylated rather than hyperphosphorylated Tau triggers a pro-inflammatory profile in microglia through the p38 MAPK pathway.
ós M Abstract Tauopathies are a broad set of neurodegenerative dementias characterized by the aggregation of Tau protein. Activated microglia and elevated levels of pro-inflammatory molecules are also pathological hallmarks of tauopathies. In these diseases, intracellular Tau is secreted to the extracellular space, where it interacts with other cells, such as neurons and glia, promoting inflammation. However, the mechanism through which extracellular Tau triggers pro-inflammatory responses in microglia remains unknown. Primary microglia cultures were treated with extracellular Tau in its hyperphosphorylated...
Source: Experimental Neurology - August 20, 2018 Category: Neurology Authors: Perea JR, Ávila J, Bolós M Tags: Exp Neurol Source Type: research

Protective effects of Withania somnifera extract in SOD1G93A mouse model of amyotrophic lateral sclerosis.
Abstract Withania somnifera (WS; commonly known as Ashwagandha or Indian ginseng) is a medicinal plant whose extracts have been in use for centuries in various regions of the world as a rejuvenator. There is now a growing body of evidence documenting neuroprotective functions of the plant extracts or its purified compounds in several models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Based on the extract's beneficial effect in a mouse model of ALS with TDP-43 proteinopathy, the current study was designed to test its efficacy in another model of familial ALS. Our results show that a...
Source: Experimental Neurology - August 19, 2018 Category: Neurology Authors: Dutta K, Patel P, Julien JP Tags: Exp Neurol Source Type: research

Bromodomain and extraterminal domain-containing protein inhibition attenuates acute inflammation after spinal cord injury.
In this study, we investigated the role of BETs in promoting inflammation in neural cells and the ability of the BET inhibitor JQ1 to decrease inflammation acutely after SCI. Expression of BET mRNA was assessed via qPCR in purified primary mouse macrophages, astrocytes, neurons, oligodendrocytes, and microglia, as well as in naïve, sham-injured, and contusion-injured mouse spinal cord. Brd2, Brd3, and Brd4 mRNA were expressed in all purified primary neural cells and in the uninjured and injured mouse spinal cord. BET inhibition significantly attenuated proinflammatory signaling in all activated cell populations in vit...
Source: Experimental Neurology - August 19, 2018 Category: Neurology Authors: Rudman MD, Choi JS, Lee HE, Tan SK, Ayad NG, Lee JK Tags: Exp Neurol Source Type: research

Muscle-dominant wild-type TDP-43 expression induces myopathological changes featuring tubular aggregates and TDP-43-positive inclusions.
Abstract Muscle histology of sporadic inclusion body myositis (sIBM) demonstrates inflammatory findings and degenerative features including accumulation of TAR DNA-binding protein of 43 kDa (TDP-43). However, whether sarcoplasmic accumulation of TDP-43 is a primary trigger of muscle degeneration or a secondary event resulting from muscle degeneration in the pathophysiology of sIBM remained unclear. Our study aimed to discover whether muscle-dominant expression of TDP-43 is a primary cause of muscle degeneration. We generated several lines of wild-type TDP-43 transgenic mice driven by a creatine kinase 8 promoter...
Source: Experimental Neurology - August 18, 2018 Category: Neurology Authors: Tawara N, Yamashita S, Kawakami K, Kurashige T, Zhang Z, Tasaki M, Yamamoto Y, Nishikami T, Doki T, Zhang X, Matsuo Y, Kimura E, Tawara A, Maeda Y, Hauschka SD, Maruyama H, Ando Y Tags: Exp Neurol Source Type: research

Recovery after spinal cord injury by modulation of the proteoglycan receptor PTP σ.
Recovery after spinal cord injury by modulation of the proteoglycan receptor PTPσ. Exp Neurol. 2018 Aug 14;: Authors: Rink S, Arnold D, Wöhler A, Bendella H, Meyer C, Manthou M, Papamitsou T, Sarikcioglu L, Angelov DN Abstract SCI is followed by dramatic upregulation of chondroitin sulfate proteoglycans (CSPGs) which limit axonal regeneration, oligodendrocyte replacement and remyelination. The recent discovery of the specific CSPGs signaling receptor protein tyrosine phosphatase sigma (RPTPσ) provided an opportunity to refine the therapeutic approach to overcome CSPGs inhibitory actio...
Source: Experimental Neurology - August 14, 2018 Category: Neurology Authors: Rink S, Arnold D, Wöhler A, Bendella H, Meyer C, Manthou M, Papamitsou T, Sarikcioglu L, Angelov DN Tags: Exp Neurol Source Type: research

Orexinergic neurons are involved in the chemosensory control of breathing during the dark phase in a Parkinson's disease model.
In conclusion, the degeneration of orexinergic neurons in this model of PD can be related to impaired chemoreceptor function in the dark phase. PMID: 30110606 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - August 12, 2018 Category: Neurology Authors: Oliveira LM, Falquetto B, Moreira TS, Takakura AC Tags: Exp Neurol Source Type: research

High glucose concentration suppresses a SIRT2 regulated pathway that enhances neurite outgrowth in cultured adult sensory neurons.
Abstract In peripheral nerve under hyperglycemic conditions high flux of d-glucose through the polyol pathway drives an aberrant redox state contributing to neurodegeneration in diabetic sensorimotor polyneuropathy (DSPN). Sirtuins, including SIRT2, detect the redox state via the NAD+/NADH ratio to regulate mitochondrial function via, in part, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). In adult dorsal root ganglia (DRG) sensory neurons mitochondrial dysfunction has been proposed as an etiological factor in dying-back neuropathy i...
Source: Experimental Neurology - August 10, 2018 Category: Neurology Authors: Schartner E, Sabbir MG, Saleh A, Silva RV, Chowdhury SR, Smith DR, Fernyhough P Tags: Exp Neurol Source Type: research

Targeting histone deacetylation for recovery of maternal deprivation-induced changes in BDNF and AKAP150 expression in the VTA.
Abstract Severe early life stressors increase the probability of developing psychiatric disorders later in life through modifications in neuronal circuits controlling brain monoaminergic signaling. Our previous work demonstrated that 24 h maternal deprivation (MD) in male Sprague Dawley rats modifies dopamine (DA) signaling from the ventral tegmental area (VTA) through changes at GABAergic synapses that were reversible by in vitro histone deacetylase (HDAC) inhibition which led to restoration of the scaffold A-kinase anchoring protein (AKAP150) signaling and subsequently recovered GABAergic plasticity (Authement...
Source: Experimental Neurology - August 10, 2018 Category: Neurology Authors: Shepard RD, Gouty S, Kassis H, Berenji A, Zhu W, Cox BM, Nugent FS Tags: Exp Neurol Source Type: research

Mutation of hop-1 and pink-1 attenuates vulnerability of neurotoxicity in C. elegans: the role of mitochondria-associated membrane proteins in Parkinsonism.
Abstract Mitochondrial dysfunction is considered as a critical mechanism in the pathogenesis of Parkinson's disease (PD). Increasing evidence supports the notion of mitochondria-associated membranes (MAMs) in mitochondrial dysfunction; yet little is known about the role of MAMs-related proteins in the pathogenesis of PD. Herein we exposed the nematode Caenorhabditis elegans to 0.5-10.0 μM rotenone (RO) or 0.2-1.6 mM paraquat (PQ) for 3 days. Our results showed that both RO and PQ induced similar Parkinsonism including motor deficits and dopaminergic degeneration. RO/PQ caused mitochondrial damages charact...
Source: Experimental Neurology - August 1, 2018 Category: Neurology Authors: Wu S, Lei L, Song Y, Liu M, Lu S, Lou D, Shi Y, Wang Z, He D Tags: Exp Neurol Source Type: research

Increased expression of toll-like receptor 3, an anti-viral signaling molecule, and related genes in alzheimer's disease brains.
Abstract The focus of this study is the expression of Toll-like receptor-3 (TLR-3), a receptor for double-stranded RNA, in human brains affected by Alzheimer's disease (AD) pathology. Toll-like receptors are a family of pattern recognition molecules primarily involved in host defenses to microbial pathogens, but roles in neurodegenerative disease have also been shown, as amyloid beta (Aβ) can be a ligand for TLR-2 and -4 and α-synuclein for TLR-1 and TLR-2, while TLR-9 activation promotes Aβ removal. However, involvement of TLR-3 in AD has not been rigorously studied. Immunohistochemical analyses i...
Source: Experimental Neurology - August 1, 2018 Category: Neurology Authors: Walker DG, Tang TM, Lue LF Tags: Exp Neurol Source Type: research

Therapeutic efficacy of regulable GDNF expression for Huntington's and Parkinson's disease by a high-induction, background-free "GeneSwitch" vector.
Therapeutic efficacy of regulable GDNF expression for Huntington's and Parkinson's disease by a high-induction, background-free "GeneSwitch" vector. Exp Neurol. 2018 Aug 01;: Authors: Cheng S, Tereshchenko J, Zimmer V, Vachey G, Pythoud C, Rey M, Liefhebber J, Raina A, Streit F, Mazur A, Bähr M, Konstantinova P, Déglon N, Kügler S Abstract Gene therapy is currently an irreversible approach, without possibilities to fine-tune or halt the expression of a therapeutic gene product. Especially when expressing neurotrophic factors to treat neurodegenerative disorders, options to r...
Source: Experimental Neurology - August 1, 2018 Category: Neurology Authors: Cheng S, Tereshchenko J, Zimmer V, Vachey G, Pythoud C, Rey M, Liefhebber J, Raina A, Streit F, Mazur A, Bähr M, Konstantinova P, Déglon N, Kügler S Tags: Exp Neurol Source Type: research

Evidence of axon connectivity across a spinal cord transection in rats treated with epidural stimulation and motor training combined with olfactory ensheathing cell transplantation.
Abstract Olfactory ensheathing cells (OECs) are unique glia that support axon outgrowth in the olfactory system, and when used as cellular therapy after spinal cord injury, improve recovery and axon regeneration. Here we assessed the effects of combining OEC transplantation with another promising therapy, epidural electrical stimulation during a rehabilitative motor task. Sprague-Dawley rats received a mid-thoracic transection and transplantation of OECs or fibroblasts (FBs) followed by lumbar stimulation while climbing an inclined grid. We injected pseudorabies virus (PRV) into hindlimb muscles 7 months post-in...
Source: Experimental Neurology - July 26, 2018 Category: Neurology Authors: Thornton MA, Mehta MD, Morad TT, Ingraham KL, Khankan RR, Griffis KG, Yeung AK, Zhong H, Roy RR, Reggie Edgerton V, Phelps PE Tags: Exp Neurol Source Type: research

A genetic deficiency in folic acid metabolism impairs recovery after ischemic stroke.
Abstract Stroke is a leading cause of disability and death world-wide and nutrition is a modifiable risk factor for stroke. Metheylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the metabolism of folic acid, a B-vitamin. In humans, a polymorphism in MTHFR (677C→T) is linked to increased risk of stroke, but the mechanisms remain unknown. The Mthfr+/- mice mimic a phenotype described in humans at bp677. Using this mouse model, the aim of this study was to investigate the impact of MTHFR deficiency on stroke outcome. Male Mthfr+/- and wildtype littermate control mice were aged (~1.5-year-old) and...
Source: Experimental Neurology - July 25, 2018 Category: Neurology Authors: Jadavji NM, Emmerson JT, Shanmugalingam U, MacFarlane AJ, Willmore WG, Smith PD Tags: Exp Neurol Source Type: research

Oligodendrocytic but not neuronal Nogo restricts corticospinal axon sprouting after CNS injury.
Abstract Recovery from injury to the central nervous system (CNS) is limited in the mammalian adult. Nonetheless, some degree of spontaneous recovery occurs after partial CNS injury. Compensatory axonal growth from uninjured neurons, termed sprouting, contributes to this naturally occurring recovery process and can be modulated by molecular intervention. Extensive studies have depicted a long-held hypothesis that oligodendrocyte-derived Nogo restricts axonal sprouting and functional recovery after CNS injury. However, cell type-specific function of Nogo in compensatory sprouting, spinal axon repair or functional r...
Source: Experimental Neurology - July 25, 2018 Category: Neurology Authors: Meves JM, Geoffroy CG, Kim ND, Kim JJ, Zheng B Tags: Exp Neurol Source Type: research

The G2019S mutation in LRRK2 imparts resiliency to kinase inhibition.
Abstract The G2019S mutation in LRRK2 is one of the most common known genetic causes of neurodegeneration and Parkinson disease (PD). LRRK2 mutations are thought to enhance LRRK2 kinase activity. Efficacious small molecule LRRK2 kinase inhibitors with favorable drug properties have recently been developed for pre-clinical studies in rodent models, and inhibitors have advanced to safety trials in humans. Rats that express human G2019S-LRRK2 protein and G2019S-LRRK2 knock-in mice provide newly characterized models to better understand the ostensible target for inhibitors. Herein, we explore the relationships between...
Source: Experimental Neurology - July 23, 2018 Category: Neurology Authors: Kelly K, Wang S, Boddu R, Liu Z, Moukha-Chafiq O, Augelli-Szafran C, West AB Tags: Exp Neurol Source Type: research

Impairment of frequency-specific responses associated with altered electrical activity patterns in auditory thalamus following focal and general demyelination.
HC Abstract Multiple sclerosis is characterized by intermingled episodes of de- and remyelination and the occurrence of white- and grey-matter damage. To mimic the randomly distributed pathophysiological brain lesions observed in MS, we assessed the impact of focal white and grey matter demyelination on thalamic function by directing targeted lysolecithin-induced lesions to the capsula interna (CI), the auditory cortex (A1), or the ventral medial geniculate nucleus (vMGN) in mice. Pathophysiological consequences were compared with those of cuprizone treatment at different stages of demyelination and remyelination...
Source: Experimental Neurology - July 23, 2018 Category: Neurology Authors: Narayanan V, Cerina M, Göbel K, Meuth P, Herrmann AM, Fernandez-Orth J, Stangel M, Gudi V, Skripuletz T, Daldrup T, Lesting J, Schiffler P, Wiendl H, Seidenbecher T, Meuth SG, Budde T, Pape HC Tags: Exp Neurol Source Type: research

Wip1 knockout inhibits neurogenesis by affecting the Wnt/ β-catenin signaling pathway in focal cerebral ischemia in mice.
Wip1 knockout inhibits neurogenesis by affecting the Wnt/β-catenin signaling pathway in focal cerebral ischemia in mice. Exp Neurol. 2018 Jul 23;: Authors: Qiu CW, Liu ZY, Hou K, Liu SY, Hu YX, Zhang L, Zhang FL, Lv KY, Kang Q, Hu WY, Ma N, Jiao Y, Bai WJ, Xiao ZC Abstract Neurogenesis correlates closely with the recovery of neural function after brain ischemia but the critical proteins and signaling pathways involved remain unclear. The phosphatase WIP1 has been shown to regulate neurogenesis in models of aging. However, it is not known if WIP1 affects neurogenesis and functional recovery after ...
Source: Experimental Neurology - July 23, 2018 Category: Neurology Authors: Qiu CW, Liu ZY, Hou K, Liu SY, Hu YX, Zhang L, Zhang FL, Lv KY, Kang Q, Hu WY, Ma N, Jiao Y, Bai WJ, Xiao ZC Tags: Exp Neurol Source Type: research

Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters.
This article reviews the current understanding of the long existing controversies regarding energy substrate and utilization in the nervous system and discusses the role of metabolic transporters in health and diseases of the nervous system. PMID: 30044944 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - July 22, 2018 Category: Neurology Authors: Jha MK, Morrison BM Tags: Exp Neurol Source Type: research

Defective daily temperature regulation in a mouse model of amyotrophic lateral sclerosis.
Abstract Current understanding of the pathogenesis of the familial form of amyotrophic lateral sclerosis has been aided by the study of transgenic mice that over-express mutated forms of the human CuZn-superoxide dismutase (SOD1) gene. While mutant SOD1 in motor neurons determines disease onset, other non-cell autonomous factors are critical for disease progression, and altered energy metabolism has been implicated as a contributing factor. Since most energy expended by laboratory mice is utilized to defend body temperature (Tb), we analyzed thermoregulation in transgenic mice carrying the G93A mutation of the hum...
Source: Experimental Neurology - July 18, 2018 Category: Neurology Authors: Braun MC, Castillo-Ruiz A, Indic P, Jung DY, Kim JK, Brown RH, Swoap SJ, Schwartz WJ Tags: Exp Neurol Source Type: research

Inhibiting Jumoji domain containing protein 3 (JMJD3) prevent neuronal apoptosis from stroke.
Abstract Control of p53 by histone methylation is closely related in the neuronal apoptosis following ischemic stroke. In mammalian cells, demethylation of methylated lysine residue of histones is catalyzed by Jumonji domain-containing proteins (JMJD) family. Among them, JMJD3 is reported to be a hypoxic target gene and expressed in all cell types of brain including neurons. However, the role of JMJD3 on process of neuronal apoptosis after ischemic stroke is still largely unknown. PCR, immunostaining and Western blotting results indicated that JMJD3 expression was upregulated in cultured neurons upon oxygen-glucos...
Source: Experimental Neurology - July 17, 2018 Category: Neurology Authors: Zhang H, Wang J, Huang J, Shi T, Ma X, Luo X, Li X, Li M Tags: Exp Neurol Source Type: research

Preterm umbilical cord blood derived mesenchymal stem/stromal cells protect preterm white matter brain development against hypoxia-ischemia.
This study examined the neuroprotective effects of allogeneic MSC, derived from preterm umbilical cord blood (UCB), in a preterm sheep model of white matter injury. METHODS: Quad-lineage differentiation, clonogenicity and self-renewal ability of UCB-derived MSC were confirmed. Chronically instrumented fetal sheep (0.7 gestation) received either 25 min hypoxia-ischemia (HI) to induce preterm brain injury, or sham-HI. Ten million MSC, or saline, were administered iv to fetuses at 12 h after HI. Fetal brains were collected 10d after HI for histopathology and immunocytochemistry. RESULTS: HI induced white matter ...
Source: Experimental Neurology - July 13, 2018 Category: Neurology Authors: Li J, Yawno T, Sutherland AE, Gurung S, Paton M, McDonald C, Tiwari A, Pham Y, Castillo-Melendez M, Jenkin G, Miller SL Tags: Exp Neurol Source Type: research

Sigma-1 receptor activation alleviates blood-brain barrier dysfunction in vascular dementia mice.
Abstract Sigma-1 receptor (Sig-1R) activation has been shown to decrease infarct volume and enhance neuronal survival after brain ischemia-reperfusion (IR) in rodent models. The present study aims to investigate first the effect of Sig-1R activation on blood-brain barrier (BBB) disruption during experimental stroke. Male C57BL/6 mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 15 min, and the worst BBB leakage was observed on the 7th day after brain IR. To confirm the BBB protective role of Sig-1R, mice were divided into five groups (sham group, BCCAO group, PRE084 group, BD1047 group...
Source: Experimental Neurology - July 10, 2018 Category: Neurology Authors: Liu DY, Chi TY, Ji XF, Liu P, Qi XX, Zhu L, Wang ZQ, Lin-Li, Chen L, Zou LB Tags: Exp Neurol Source Type: research

Alternative RNA splicing associated with axon regeneration after rat peripheral nerve injury.
Abstract The intrinsic axon regeneration capacity is crucial for peripheral nerve regeneration after injury. Identifying key molecules involved in this process makes great contribution to the investigation of peripheral nerve injury repair. Alternative splicing (AS) is an important regulation mode of eukaryotic gene expression, which has been widely studied both in physiological and pathological processes. However, less is known about the role of AS in peripheral nerve regeneration. In this work, to identify the AS events associated with axon regeneration capacity, we analyzed the AS events during sciatic nerve in...
Source: Experimental Neurology - July 4, 2018 Category: Neurology Authors: Mao S, Zhang S, Zhou Z, Shi X, Huang T, Feng W, Yao C, Gu X, Yu B Tags: Exp Neurol Source Type: research

MANF protects dopamine neurons and locomotion defects from a human α-synuclein induced Parkinson's disease model in C. elegans by regulating ER stress and autophagy pathways.
MANF protects dopamine neurons and locomotion defects from a human α-synuclein induced Parkinson's disease model in C. elegans by regulating ER stress and autophagy pathways. Exp Neurol. 2018 Jun 27;: Authors: Zhang Z, Shen Y, Luo H, Zhang F, Jing L, Wu Y, Xia X, Song Y, Li W, Jin L Abstract There are many studies have demonstrated that mesencephalic astrocyte-derived neurotrophic factor (MANF) has been shown protective effects on neurotoxin based models of Parkinson's disease (PD). It still remains unclear whether MANF can rescue dopaminergic (DA) neurons in an α-synuclein model. Glial ce...
Source: Experimental Neurology - June 27, 2018 Category: Neurology Authors: Zhang Z, Shen Y, Luo H, Zhang F, Jing L, Wu Y, Xia X, Song Y, Li W, Jin L Tags: Exp Neurol Source Type: research

Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model.
In this study, we have undertaken behavioural phenotyping, magnetic resonance imaging (MRI) and isolation of S-acylated proteins to investigate the effect of disruption of the Zdhhc9 gene in mice in a C57BL/6 genetic background. Zdhhc9 mutant male mice exhibit a range of abnormalities compared with their wild-type littermates: altered behaviour in the open-field test, elevated plus maze and acoustic startle test that is consistent with a reduced anxiety level; a reduced hang time in the hanging wire test that suggests underlying hypotonia but which may also be linked to reduced anxiety; deficits in the Morris water maze te...
Source: Experimental Neurology - June 23, 2018 Category: Neurology Authors: Kouskou M, Thomson DM, Brett RR, Wheeler L, Tate RJ, Pratt JA, Chamberlain LH Tags: Exp Neurol Source Type: research

Altered glutamate response and calcium dynamics in iPSC-derived striatal neurons from XDP patients.
egner F Abstract X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disorder endemic to Panay Island (Philippines). Patients present with generalizing dystonia and parkinsonism. Genetic changes surrounding the TAF1 (TATA-box binding protein associated factor 1) gene have been associated with XDP inducing a degeneration of striatal spiny projection neurons. There is little knowledge about the pathophysiology of this disorder. Our objective was to generate and analyze an in-vitro model of XDP based on striatal neurons differentiated from induced pluripotent stem cells (iPSC). We generated iPSC from patient ...
Source: Experimental Neurology - June 23, 2018 Category: Neurology Authors: Capetian P, Stanslowsky N, Bernhardi E, Grütz K, Domingo A, Brüggemann N, Naujock M, Seibler P, Klein C, Wegner F Tags: Exp Neurol Source Type: research

RhoA regulates Schwann cell differentiation through JNK pathway.
Abstract RhoA is a small GTPase that regulates many functions of mammalian cells via actin reorganization. Lots of studies uncovered that its activation acts as a major negative regulator of neurite extension, and inhibition of RhoA activity or reduction of its expression can promote neuron survival and axonal regeneration. However, little is known about whether RhoA also exerts important functions on Schwann cells (SCs) which are the glial cells of the peripheral nervous system (PNS). Recently, we reported that RhoA plays important roles in the proliferation, migration and myelination. In the present study, using...
Source: Experimental Neurology - June 22, 2018 Category: Neurology Authors: Wen J, Tan D, Li L, Wang X, Pan M, Guo J Tags: Exp Neurol Source Type: research

Myelinated axons fail to develop properly in a genetically authentic mouse model of Charcot-Marie-Tooth disease type 2E.
Abstract We have analyzed a mouse model of Charcot-Marie-Tooth disease 2E (CMT2E) harboring a heterozygous p.Asn98Ser (p.N98S) Nefl mutation, whose human counterpart results in a severe, early-onset neuropathy. Behavioral, electrophysiological, and pathological analyses were done on separate cohorts of NeflN98S/+ mutant mice and their wild type Nefl+/+ littermates between 8 and 48 weeks of age. The motor performance of NeflN98S/+ mice, as evidenced by altered balance and gait measures, was impaired at every age examined (from 6 to 25 weeks of age). At all times examined, myelinated axons were smaller and conta...
Source: Experimental Neurology - June 22, 2018 Category: Neurology Authors: Lancaster E, Li J, Hanania T, Liem R, Scheideler MA, Scherer SS Tags: Exp Neurol Source Type: research

Chronic traffic noise stress accelerates brain impairment and cognitive decline in mice.
Abstract Although traffic noise exposure is a well-known environmental pollutant whose negative health effect has been discussed in different aspects of the human life, only a few animal studies have tackled this issue as a cohort study, which is not feasible to be addressed in human studies. In addition to the deleterious impact of the daytime noise on well-being, chronic nocturnal noise can also disturb sleep and affects physical and mental health, but to date, little research has examined the neurobiological effects light/dark cycles of traffic noise exposure. We investigated the effects of light/dark cycles an...
Source: Experimental Neurology - June 21, 2018 Category: Neurology Authors: Jafari Z, Kolb BE, Mohajerani MH Tags: Exp Neurol Source Type: research

The human motor neuron axonal transcriptome is enriched for transcripts related to mitochondrial function and microtubule-based axonal transport.
MA Abstract Local axonal translation of specific mRNA species plays an important role in axon maintenance, plasticity during development and recovery from injury. Recently, disrupted axonal mRNA transport and translation have been linked to neurodegenerative disorders. To identify mRNA species that are actively transported to axons and play an important role in axonal physiology, we mapped the axonal transcriptome of human induced pluripotent stem cell (iPSC)-derived motor neurons using permeable inserts to obtain large amounts of enriched axonal material for RNA isolation and sequencing. Motor neurons from healt...
Source: Experimental Neurology - June 20, 2018 Category: Neurology Authors: Maciel R, Bis D, Rebelo AP, Saghira C, Züchner S, Saporta MA Tags: Exp Neurol Source Type: research

Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis.
Abstract Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative syndrome characterized by the systemic loss of motor neurons with prominent astrocytosis and microgliosis in the spinal cord and brain. Astrocytes play an essential role in maintaining extracellular microenvironments that surround motor neurons, and are activated by various insults. Growing evidence points to a non-cell autonomous neurotoxicity caused by chronic and sustained astrocytic activation in patients with neurodegenerative diseases, including ALS. However, the mechanisms that underlie the harmful effects of astrocytosi...
Source: Experimental Neurology - June 19, 2018 Category: Neurology Authors: Shijo T, Warita H, Suzuki N, Ikeda K, Mitsuzawa S, Akiyama T, Ono H, Nishiyama A, Izumi R, Kitajima Y, Aoki M Tags: Exp Neurol Source Type: research

Memantine rescues prenatal citalopram exposure-induced striatal and social abnormalities in mice.
Abstract Prenatal exposure to citalopram (CTM), an antidepressant drug, has been associated with altered behavior, including autism-like symptoms in both human and rodent offspring. However, the neurological basis underlying these abnormal behaviors is not well understood. Here, we examined behavioral, morphological, and biochemical alterations in the male and female offspring of C57BL/6 mouse mothers that had been exposed to CTM during the last trimester of gestation. We observed abnormal behavior such as anxiety, altered locomotion and disordered social interactions in 2-5 month old offspring with prenatal CTM...
Source: Experimental Neurology - June 15, 2018 Category: Neurology Authors: Zahra A, Jiang J, Chen Y, Long C, Yang L Tags: Exp Neurol Source Type: research

Intravenous xenogeneic human cardiosphere-derived cell extracellular vesicles (exosomes) improves behavioral function in small-clot embolized rabbits.
In this report, we show that intravenous (IV) CDC-EVs (0.75 mg/kg) administered 1-hour post-embolization significantly attenuate behavioral deficits following an embolic stroke in rabbits. In CDC-EV-treated rabbits, P50 (3.63 ± 1.27 mg, n = 24) was increased by 245% over vehicle control (1.05 ± 0.15 mg, n = 24); by comparison, rt-PA increased P50 by 91% (2.01 ± 0.24 mg, n = 23). Importantly, the therapy was also without adverse effects on intracerebral hemorrhage or survival rate of embolized rabbits. Thus, as a first step toward widespread use, CDC-EVs, given adjunctive...
Source: Experimental Neurology - June 13, 2018 Category: Neurology Authors: Lapchak PA, Boitano PD, de Couto G, Marbán E Tags: Exp Neurol Source Type: research