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  • Striatal glutamate delta-1 receptor regulates behavioral flexibility and thalamostriatal connectivity
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-13
    Jinxu Liu; Gajanan P. Shelkar; Pauravi J. Gandhi; Dinesh Y. Gawande; Andrew Hoover; Rosa M. Villalba; Ratnamala Pavuluri; Yoland Smith; Shashank M. Dravid
    更新日期:2020-01-13
  • APOE alters glucose flux through central carbon pathways in astrocytes
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-11
    Holden C. Williams; Brandon C. Farmer; Maggie A. Piron; Adeline E. Walsh; Ron Bruntz; Matthew Gentry; Ramon C. Sun; Lance A. Johnson
    更新日期:2020-01-11
  • Simultaneous mass spectrometry imaging of multiple neuropeptides in the brain and alterations induced by experimental parkinsonism and L-DOPA therapy
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-10
    Heather Hulme; Elva Fridjonsdottir; Halla Gunnarsdottir; Theodosia Vallianatou; Xiaoqun Zhang; Henrik Wadensten; Reza Shariatgorji; Anna Nilsson; Erwan Bezard; Per Svenningsson; Per E. Andrén

    Neuropeptides are important signalling molecules in the brain and alterations in their expression levels have been linked to neurological disorders such as Parkinson's disease. It is challenging to map neuropeptide changes across and within brain regions because of their low in vivo concentrations and complex post-translational processing. Consequently, the role of neuropeptides in Parkinson's disease is not well understood. Thus, we have developed and validated a method to image multiple neuropeptides simultaneously in both rat and primate brain tissue sections by matrix-assisted laser desorption-ionization mass spectrometry imaging at high lateral resolution. Using a unilateral 6-hydroxydopamine rat model of Parkinson's disease, we imaged changes in enkephalins, dynorphins, tachykinins and neurotensin associated with the dopaminergic denervation and L-DOPA treatment in multiple brain regions. L-DOPA administration significantly affected neuropeptides in the globus pallidus, while neuropeptides in the caudate-putamen were mostly affected by dopamine depletion. Using high lateral resolution imaging, we observed an increase of neurotensin in the dorsal sub-region of the globus pallidus after dopamine depletion. This study highlights the capacity of mass spectrometry imaging to elucidate the dynamics of neuropeptide signalling during Parkinson's disease and its treatment.

    更新日期:2020-01-11
  • 更新日期:2020-01-11
  • Fragile X syndrome and associated disorders: Clinical aspects and pathology
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-10
    Maria Jimena Salcedo-Arellano; Brett Dufour; Yingratana McLennan; Veronica Martinez-Cerdeno; Randi Hagerman

    This review aims to assemble many years of research and clinical experience in the fields of neurodevelopment and neuroscience to present an up-to-date understanding of the clinical presentation, molecular and brain pathology associated with Fragile X syndrome, a neurodevelopmental condition that develops with the full mutation of the FMR1 gene, located in the q27.3 loci of the X chromosome, and Fragile X-associated tremor/ataxia syndrome a neurodegenerative disease experienced by aging premutation carriers of the FMR1 gene. It is important to understand that these two syndromes have a very distinct clinical and pathological presentation while sharing the same origin: the mutation of the FMR1 gene; revealing the complexity of expansion genetics.

    更新日期:2020-01-11
  • Reprint of: Manipulation of microbiota reveals altered callosal myelination and white matter plasticity in a model of Huntington disease
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-10
    Carola I. Radulescu; Marta Garcia-Miralles; Harwin Sidik; Costanza Ferrari Bardile; Nur Amirah Binte Mohammad Yusof; Hae Ung Lee; Eliza Xin Pei Ho; Collins Wenhan Chu; Emma Layton; Donovan Low; Paola Florez De Sessions; Sven Pettersson; Florent Ginhoux; Mahmoud A. Pouladi

    Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and oligodendroglial population dynamics in the mixed-sex BACHD mouse model of HD. Ultrastructural analysis of myelin in the corpus callosum revealed alterations of myelin thickness in BACHD GF compared to specific-pathogen free (SPF) mice, whereas no differences were observed between wild-type (WT) groups. In contrast, myelin compaction was altered in all groups when compared to WT SPF animals. Levels of myelin-related proteins were generally reduced, and the number of mature oligodendrocytes was decreased in the prefrontal cortex under GF compared to SPF conditions, regardless of genotype. Minor differences in commensal bacteria at the family and genera levels were found in the gut microbiota of BACHD and WT animals housed in standard living conditions. Our findings indicate complex effects of a germ-free status on myelin-related characteristics, and highlight the adaptive properties of myelination as a result of environmental manipulation.

    更新日期:2020-01-11
  • Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-10
    Trisha R. Stankiewicz; Claudia Pena; Ron J. Bouchard; Daniel A. Linseman

    Rho GTPases play a central role in neuronal survival; however, the antagonistic relationship between Rac and Rho in the regulation of motor neuron survival remains poorly defined. In the current study, we demonstrate that treatment with NSC23766, a selective inhibitor of the Rac-specific guanine nucleotide exchange factors, Tiam1 and Trio, is sufficient to induce the death of embryonic stem cell (ESC)-derived motor neurons. The mode of cell death is primarily apoptotic and is characterized by caspase-3 activation, de-phosphorylation of ERK5 and AKT, and nuclear translocation of the BH3-only protein Bad. As opposed to the inhibition of Rac, motor neuron cell death is also induced by constitutive activation of Rho, via a mechanism that depends on Rho kinase (ROCK) activity. Investigation of Rac and Rho in the G93A mutant, human Cu, Zn-superoxide dismutase (hSOD1) mouse model of amyotrophic lateral sclerosis (ALS), revealed that active Rac1-GTP is markedly decreased in spinal cord motor neurons of transgenic mice at disease onset and end-stage, when compared to age-matched wild type (WT) littermates. Furthermore, although there is no significant change in active RhoA-GTP, total RhoB displays a striking redistribution from motor neuron nuclei in WT mouse spinal cord to motor neuron axons in end-stage G93A mutant hSOD1 mice. Collectively, these data suggest that the intricate balance between pro-survival Rac signaling and pro-apoptotic Rho/ROCK signaling is critical for motor neuron survival and therefore, disruption in the balance of their activities and/or localization may contribute to the death of motor neurons in ALS.

    更新日期:2020-01-11
  • Every-other-day feeding exacerbates inflammation and neuronal deficits in 5XFAD mouse model of Alzheimer's disease
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-10
    Divna Lazic; Vesna Tesic; Mirna Jovanovic; Marjana Brkic; Desanka Milanovic; Berislav V. Zlokovic; Selma Kanazir; Milka Perovic

    Food restriction has been widely associated with beneficial effects on brain aging and age-related neurodegenerative diseases such as Alzheimer's disease. However, previous studies on the effects of food restriction on aging- or pathology-related cognitive decline are controversial, emphasizing the importance of the type, onset and duration of food restriction. In the present study, we assessed the effects of preventive every-other-day (EOD) feeding regimen on neurodegenerative phenotype in 5XFAD transgenic mice, a commonly used mouse model of Alzheimer's disease. EOD feeding regimen was introduced to transgenic female mice at the age of 2 months and the effects on amyloid-β (Aβ) accumulation, gliosis, synaptic plasticity, and blood-brain barrier breakdown were analyzed in cortical tissue of 6-month-old animals. Surprisingly, significant increase of inflammation in the cortex of 5XFAD fed EOD mice was observed, reflected by the expression of microglial and astrocytic markers. This increase in reactivity and/or proliferation of glial cells was accompanied by an increase in proinflammatory cytokine TNF-α, p38 MAPK and EAAT2, and a decrease in GAD67. NMDA receptor subunit 2B, related to glutamate excitotoxicity, was increased in the cortex of 5XFAD-EOD mice indicating additional alterations in glutamatergic signaling. Furthermore, 4 months of EOD feeding regimen had led to synaptic plasticity proteins reduction and neuronal injury in 5XFAD mice. However, EOD feeding regimen did not affect Aβ load and blood-brain barrier permeability in the cortex of 5XFAD mice. Our results demonstrate that EOD feeding regimen exacerbates Alzheimer's disease-like neurodegenerative and neuroinflammatory changes irrespective of Aβ pathology in 5XFAD mice, suggesting that caution should be paid when using food restrictions in the prodromal phase of this neurodegenerative disease.

    更新日期:2020-01-11
  • Insulin deficiency promotes formation of toxic amyloid-β42 conformer co-aggregating with hyper-phosphorylated tau oligomer in an Alzheimer's disease model
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-10
    Tomohiro Imamura; Yuki T. Yanagihara; Yasumasa Ohyagi; Norimichi Nakamura; Kyoko M. Iinuma; Ryo Yamasaki; Hirohide Asai; Masahiro Maeda; Kazuma Murakami; Kazuhiro Irie; Jun-ichi Kira

    The toxic conformer of amyloid β-protein (Aβ) ending at 42 (Aβ42), which contains a unique turn conformation at amino acid residue positions 22 and 23 and tends to form oligomers that are neurotoxic, was reported to play a critical role in the pathomechanisms of Alzheimer's disease (AD), in which diabetes mellitus (DM)-like mechanisms are also suggested to be operative. It remains to be established whether the attenuation of insulin signaling is involved in an increase of toxic Aβ42 conformer levels. The present study investigated the association between impaired insulin metabolism and formation of toxic Aβ42 conformers in the brains of an AD mouse model. In particular, we studied whether insulin deficiency or resistance affected the formation of toxic Aβ42 conformers in vivo. We induced insulin deficiency and resistance in 3xTg-AD mice, a mouse AD model harboring two familial AD-mutant APP (KM670/671NL) and PS1 (M146 V) genes and a mutant TAU (P301L) gene, by streptozotocin (STZ) injection and a high fructose diet (HFuD), respectively. Cognitive impairment was significantly worsened by STZ injection but not by HFuD. Dot blot analysis revealed significant increases in total Aβ42 levels and the ratio of toxic Aβ42 conformer/total Aβ42 in STZ-treated mice compared with control and HFuD-fed mice. Immunostaining showed the accumulation of toxic Aβ42 conformers and hyper-phosphorylated tau protein (p-tau), which was more prominent in the cortical and hippocampal neurons of STZ-treated mice compared with HFuD-fed and control mice. HFuD-fed mice showed only a mild-to-moderate increase of these proteins compared with controls. Toxic Aβ42 conformers were co-localized with p-tau oligomers (Pearson's correlation coefficient = 0.62) in the hippocampus, indicating their co-aggregation. Toxic Aβ42 conformer levels were inversely correlated with pancreatic insulin secretion capacity as shown by fasting immunoreactive insulin levels in STZ-treated mice (correlation coefficient = −0.5879, p = .04441), but not HFuD-fed mice, suggesting a decrease in serum insulin levels correlates with toxic Aβ42 conformer formation. Levels of p-Akt and phosphorylated glycogen synthase kinase-3β measured by a homogeneous time-resolved fluorescence assay were significantly lower in STZ-treated mice than in HFuD-fed mice, suggesting a greater inhibition of brain insulin signaling by STZ than HFuD, although both levels were significantly decreased in these groups compared with controls. Iba1-positive and NOS2-positive areas in the cortex and hippocampus were significantly increased in STZ-treated mice and to a lesser extent in HFuD-fed mice compared with controls. These findings suggest that insulin deficiency rather than insulin resistance and the resultant impairment of brain insulin signaling facilitates the formation of toxic Aβ42 conformer and its co-aggregation with p-tau oligomers, and that insulin deficiency is an important pathogenic factor in the progression of AD.

    更新日期:2020-01-11
  • Defining molecular identity and fates of CNS-border associated macrophages after ischemic stroke in rodents and humans
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-08
    Wenson D. Rajan; Bartosz Wojtas; Bartlomiej Gielniewski; Francesc Miró-Mur; Jordi Pedragosa; Malgorzata Zawadzka; Paulina Pilanc; Anna M. Planas; Bozena Kaminska

    Central nervous system (CNS)-border associated macrophages (BAMs) maintain their steady-state population during adulthood and are not replaced by circulating monocytes under physiological conditions. Their roles in CNS integrity and functions under pathological conditions remain largely unknown. Until recently, BAMs and microglia could not be unequivocally distinguished due to expression of common macrophage markers. We investigated the transcriptional profiles of immunosorted BAMs from rat sham-operated and ischemic brains using RNA sequencing. We found that BAMs express the distinct transcriptional signature than microglia and infiltrating macrophages. The enrichment of functional groups associated with the cell cycle in CD163+ cells isolated 3 days after the ischemic injury indicates the proliferative capacity of these cells. The increased number of CD163+ cells 3 days post-ischemia was corroborated by flow cytometry and detecting the increased number of CD163+ cells positive for a proliferation marker Ki67 at perivascular spaces. CD163+ cells in the ischemic brains up-regulated many inflammatory genes and parenchymal CD163+ cells expressed iNOS, which indicates acquisition of a pro-inflammatory phenotype. In mice, BAMs typically express CD206 and we found a subset of these cells expressing CD169. Chimeric mice generated by transplanting bone marrow of donor Cx3cr1gfpCCR2rfp mice to wild type hosts showed an increased number of CX3CR1+CD169+ perivascular macrophages 3 days post-ischemia. Furthermore, these cells accumulated in the brain parenchyma and we detected replacement of perivascular macrophages by peripheral monocytic cells in the sub-acute phase of stroke. In line with the animal results, post-mortem brain samples from human ischemic stroke cases showed time-dependent accumulation of CD163+ cells in the ischemic parenchyma. Our findings indicate a unique transcriptional signature of BAMs, their local proliferation and migration of inflammatory BAMs to the brain parenchyma after stroke in animal models and humans.

    更新日期:2020-01-09
  • Parkin deficiency perturbs striatal circuit dynamics
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-07
    Magdalena K. Baaske; Edgar R. Kramer; Durga Praveen Meka; Gerhard Engler; Andreas K. Engel; Christian K.E. Moll

    Loss-of-function mutations in the parkin-encoding PARK2 gene are a frequent cause of young-onset, autosomal recessive Parkinson's disease (PD). Parkin knockout mice have no nigro-striatal neuronal loss but exhibit abnormalities of striatal dopamine transmission and cortico-striatal synaptic function. How these predegenerative changes observed in vitro affect neural dynamics at the intact circuit level, however, remains hitherto elusive. Here, we recorded from motor cortex, striatum and globus pallidus (GP) of anesthetized parkin-deficient mice to assess cortex-basal ganglia circuit dynamics and to dissect cell type-specific functional connectivity in the presymptomatic phase of genetic PD. While ongoing activity of presumed striatal spiny projection neurons and their downstream counterparts in the GP was not different from controls, parkin deficiency had a differential impact on striatal interneurons: In parkin-mutant mice, tonically active neurons displayed elevated activity levels. Baseline firing rates of transgenic striatal fast spiking interneurons (FSI), on the contrary, were reduced and the correlational structure of the FSI microcircuitry was disrupted. The entire transgenic striatal microcircuit showed enhanced and phase-shifted phase coupling to slow (1-3 Hz) cortical population oscillations. Unexpectedly, local field potentials recorded from striatum and GP of parkin-mutant mice robustly displayed amplified beta oscillations (~22 Hz), phase-coupled to cortex. Parkin deficiency selectively increased spike-field coupling of FSIs to beta oscillations. Our findings suggest that loss of parkin function leads to amplifications of synchronized cortico-striatal oscillations and an intrastriatal reconfiguration of interneuronal circuits. This presymptomatic disarrangement of dynamic functional connectivity may precede nigro-striatal neurodegeneration and predispose to imbalance of striatal outflow accompanying symptomatic PD.

    更新日期:2020-01-07
  • APOE in the normal brain
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-03
    Sarah A. Flowers; G. William Rebeck

    The APOE4 protein affects the primary neuropathological markers of Alzheimer's disease (AD): amyloid plaques, neurofibrillary tangles, and gliosis. These interactions have been investigated to understand the strong effect of APOE genotype on risk of AD. However, APOE genotype has strong effects on processes in normal brains, in the absence of the hallmarks of AD. We propose that CNS APOE is involved in processes in the normal brains that in later years apply specifically to processes of AD pathogenesis. We review the differences of the APOE protein found in the CNS compared to the plasma, including post-translational modifications (glycosylation, lipidation, multimer formation), focusing on ways that the common APOE isoforms differ from each other. We also review structural and functional studies of young human brains and control APOE knock-in mouse brains. These approaches demonstrate the effects of APOE genotype on microscopic neuron structure, gross brain structure, and behavior, primarily related to the hippocampal areas. By focusing on the effects of APOE genotype on normal brain function, approaches can be pursued to identify biomarkers of APOE dysfunction, to promote normal functions of the APOE4 isoform, and to prevent the accumulation of the pathologic hallmarks of AD with aging.

    更新日期:2020-01-04
  • The drug adaptaquin blocks ATF4/CHOP-dependent pro-death Trib3 induction and protects in cellular and mouse models of Parkinson's disease
    Neurobiol. Dis. (IF 5.160) Pub Date : 2020-01-03
    Pascaline Aimé; Saravanan S. Karuppagounder; Apeksha Rao; Yingxin Chen; Robert E. Burke; Rajiv R. Ratan; Lloyd A. Greene
    更新日期:2020-01-04
  • Autism-associated mutations in the CaVβ2 calcium-channel subunit increase Ba2+-currents and lead to differential modulation by the RGK-protein Gem
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-27
    Patrick Despang; Sarah Salamon; Alexandra Breitenkamp; Elza Kuzmenkina; Stefan Herzig; Jan Matthes

    Voltage-gated calcium-channels (VGCCs) are heteromers consisting of several subunits. Mutations in the genes coding for VGCC subunits have been reported to be associated with autism spectrum disorder (ASD). In a previous study, we identified electrophysiologically relevant missense mutations of CaVβ2 subunits of VGCCs. From this, we derived the hypothesis that several CaVβ2-mutations associated with ASD show common features sensitizing LTCCs and/or enhancing currents. Using a CaVβ2d backbone, we performed extensive whole-cell and single-channel patch-clamp analyses of Ba2+ currents carried by Cav1.2 pore subunits co-transfected with the previously described CaVβ2 mutations (G167S, S197F) as well as a recently identified point mutation (V2D). Furthermore, the interaction of the mutated CaVβ2d subunits with the RGK protein Gem was analyzed by co-immunoprecipitation assays and electrophysiological studies. Patch-clamp analyses revealed that all mutations increase Ba2+ currents, e.g. by decreasing inactivation or increasing fraction of active sweeps. All CaVβ2 mutations interact with Gem, but differ in the extent and characteristics of modulation by this RGK protein (e.g. decrease of fraction of active sweeps: CaVβ2d_G167S > CaVβ2d_V2D > CaVβ2d_S197F). In conclusion, patch-clamp recordings of ASD-associated CaVβ2d mutations revealed differential modulation of Ba2+ currents carried by CaV1.2 suggesting kind of an “electrophysiological fingerprint” each. The increase in current finally observed with all CaVβ2d mutations analyzed might contribute to the complex pathophysiology of ASD and by this indicate a possible underlying molecular mechanism.

    更新日期:2019-12-27
  • Four-month treadmill exercise prevents the decline in spatial learning and memory abilities and the loss of spinophilin-immunoreactive puncta in the hippocampus of APP/PS1 transgenic mice
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-27
    Lei Zhang; Wei Tang; Feng-lei Chao; Chun-ni Zhou; Lin Jiang; Yi Zhang; Xin Liang; Jing Tang; Ying-qiang Qi; Hao Yang; Qi He; Shan-shan Zhang; Lin Zhu; Yan Peng; Yong Tang

    Background Previous studies have reported that exercise could improve the plasticity of hippocampal synapses. However, the effects of exercise on synapses in the hippocampus in Alzheimer's disease (AD) are not completely known. Methods In this study, thirty 12-month-old male APP/PS1 double transgenic mice were randomly divided into a sedentary group (n = 15) and a running group (n = 15). Fifteen 12-month-old male wild-type littermates were assigned to the control group (n = 15). While running mice were assigned to treadmill running for four months, the control mice and sedentary mice did not run during the study period. After Morris water maze testing, five mice in each group were randomly selected for a stereological assessment of spinophilin-immunoreactive puncta in the CA1, CA2–3 and dentate gyrus (DG) of the hippocampus. Results Morris water maze testing revealed that while the learning and memory abilities in sedentary APP/PS1 mice were significantly worse than those in wild-type control mice, the learning and memory abilities in running APP/PS1 mice were significantly better than those in sedentary APP/PS1 mice. The stereological results showed that the spinophilin-immunoreactive puncta numbers of the CA1, CA2–3 and DG in the hippocampus of sedentary APP/PS1 mice were significantly lower than those of wild-type control mice and that the numbers of these spines in the CA1, CA2–3 and DG in the hippocampus of running APP/PS1 mice were significantly higher than those of sedentary APP/PS1 mice. Moreover, a running-induced improvement in spatial learning and memory abilities was significantly correlated with running-induced increases in the spinophilin-immunoreactive puncta numbers in the CA1 and DG of the hippocampus. Conclusions Four-month treadmill exercise induced a significant improvement in spatial learning and memory abilities and a significant increase in the number of spinophilin-immunoreactive puncta of the CA1, CA2–3 and DG in the hippocampus of APP/PS1 mice. Running-induced improvements in spatial learning and memory abilities were significantly correlated with running-induced increases in the spinophilin-immunoreactive puncta numbers in the CA1 and DG of the hippocampus.

    更新日期:2019-12-27
  • Glycogen synthase kinase 3 β activity is essential for Polo-like kinase 2- and Leucine-rich repeat kinase 2-mediated regulation of α-synuclein
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-24
    Rikke H. Kofoed; Cristine Betzer; Nelson Ferreira; Poul Henning Jensen

    Parkinson's disease (PD) is a currently incurable disease and the number of patients is expected to increase due to the extended human lifespan. α-Synuclein is a pathological hallmark of PD and variations and triplications of the gene encoding α-synuclein are strongly correlated with the risk of developing PD. Decreasing α-synuclein is therefore a promising therapeutic strategy for the treatment of PD. We have previously demonstrated that Polo-like kinase 2 (PLK-2) regulates α-synuclein protein levels by modulating the expression of α-synuclein mRNA. In this study, we further expand the knowledge on this pathway and show that it depends on down-stream modulation of Glycogen-synthase kinase 3 β (GSK-3β). We show that PLK-2 inhibition only increases α-synuclein levels in the presence of active GSK-3β in both cell lines and primary neuronal cultures. Furthermore, direct inhibition of GSK-3β decreases α-synuclein protein and mRNA levels in our cell model and overexpression of Leucine-rich repeat kinase 2, known to activate GSK-3β, increases α-synuclein levels. Finally, we show an increase in endogenous α-synuclein in primary neurons when increasing GSK-3β activity. Our findings demonstrate a not previously described role of endogenous GSK-3β activity in the PLK-2 mediated regulation of α-synuclein levels. This finding opens up the possibility of GSK-3β as a novel target for decreasing α-synuclein levels by the use of small molecule compounds, hereby serving as a disease modulating strategy.

    更新日期:2019-12-25
  • Loss of presenilin 2 age-dependently alters susceptibility to acute seizures and kindling acquisition
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-17
    Megan Beckman; Kevin Knox; Zachery Koneval; Carole Smith; Suman Jayadev; Melissa Barker-Haliski

    Patients with Alzheimer's disease (AD) experience seizures at higher rates than the general population of that age, suggesting an underexplored role of hyperexcitability in AD. Genetic variants in presenilin (PSEN) 1 and 2 genes lead to autosomal dominant early-onset AD (ADAD); patients with PSEN gene variants also report seizures. Pharmacological control of seizures in AD may be disease-modifying. Preclinical efficacy of FDA-approved antiseizure drugs (ASDs) is well defined in young adult rodents; however, the efficacy of ASDs in aged rodents with chronic seizures is less clear. The mechanism by which ADAD genes lead to AD remains unclear, and even less studied is the pathogenesis of epilepsy in AD. PSEN variants generally all result in a biochemical loss of function (De Strooper, 2007). We herein determined whether well-established models of acute and chronic seizure could be used to explore the relationship between AD genes and seizures through investigating whether loss of normal PSEN2 function age-dependently influenced susceptibility to seizures and/or corneal kindling acquisition. PSEN2 knockout (KO) and age-matched wild-type (WT) mice were screened from 2- to 10-months-old to establish age-dependent focal seizure threshold. Additionally, PSEN2 KO and WT mice aged 2- and 8-months-old underwent corneal kindling such that mice were aged 3- and 9-months old at the beginning of ASD efficacy testing. We then defined the dose-dependent efficacy of mechanistically distinct ASDs on kindled seizures of young versus aged mice to better understand the applicability of corneal kindling to real-world use for geriatric patients. PSEN2 KO mice demonstrated early-life reductions in seizure threshold. However, kindling acquisition was delayed in 2-month-old PSEN2 KO versus WT mice. Young male WT mice took 24.3 ± 1.3 (S.E.M.) stimulations to achieve kindling criterion, whereas age-matched PSEN2 KO male mice took 41.2 ± 1.1 stimulations (p < .0001). The rate of kindling acquisition of 8-month-old mice was no longer different from WT. This study demonstrates that loss of normal PSEN2 function is associated with age-dependent changes in the in vivo susceptibility to acute seizures and kindling. Loss of normal PSEN2 function may be an underexplored molecular contributor to seizures. The use of validated models of chronic seizures in aged rodents may uncover age-related changes in susceptibility to epileptogenesis and/or ASD efficacy in mice with AD-associated genotypes, which may benefit the management of seizures in AD.

    更新日期:2019-12-18
  • Behavioral defects associated with amygdala and cortical dysfunction in mice with seeded α-synuclein inclusions
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-16
    Lindsay E. Stoyka; Andrew E. Arrant; Drake R. Thrasher; Dreson L. Russell; Jennifer Freire; Casey L. Mahoney; Ashwin Narayanan; Aseel G. Dib; David G. Standaert; Laura A. Volpicelli-Daley

    Parkinson's disease (PD) is defined by motor symptoms such as tremor at rest, bradykinesia, postural instability, and stiffness. In addition to the classical motor defects that define PD, up to 80% of patients experience cognitive changes and psychiatric disturbances, referred to as PD dementia (PDD). Pathologically, PD is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein. Much of PD research has focused on the role of α-synuclein aggregates in degeneration of SNpc dopamine neurons because of the impact of loss of striatal dopamine on the classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the cortex and limbic brain regions such as the amygdala, which may contribute to non-motor phenotypes. Little is known about the consequences of α-synuclein inclusions in these brain regions, or in neuronal subtypes other than dopamine neurons. This project expands knowledge on how α-synuclein inclusions disrupt behavior, specifically non-motor symptoms of synucleinopathies. We show that bilateral injections of fibrils into the striatum results in robust bilateral α-synuclein inclusion formation in the cortex and amygdala. Inclusions in the amygdala and prefrontal cortex primarily localize to excitatory neurons. Unbiased stereology shows no significant loss of neurons in the amygdala or cortex. Fibril injected mice show defects in a social dominance behavioral task and fear conditioning; tasks that are associated with prefrontal cortex and amygdala function. Together, these observations suggest that seeded α-synuclein inclusion formation impairs behaviors associated with cortical and amygdala function, without causing cell loss, in brain areas that may play important roles in the complex cognitive features of PDD.

    更新日期:2019-12-17
  • Implications of gut microbiota dysbiosis and metabolic changes in prion disease
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-16
    Dongming Yang; Deming Zhao; Syed Zahid Ali Shah; Wei Wu; Mengyu Lai; Xixi Zhang; Jie Li; Zhiling Guan; Huafen Zhao; Wen Li; Hongli Gao; Xiangmei Zhou; Lifeng Yang

    Evidence of the gut microbiota influencing neurodegenerative diseases has been reported for several neural diseases. However, there is little insight regarding the relationship between the gut microbiota and prion disease. Here, using fecal samples of 12 prion-infected mice and 25 healthy controls, we analyzed the structure of the gut microbiota and metabolic changes by 16S rRNA sequencing and LC-MS–based metabolomics respectively as multi-omic analyses. Additionally, SCFAs and common amino acids were detected by GC–MS and UPLC respectively. Enteric changes induced by prion disease affected both structure and abundances of the gut microbiota. The gut microbiota of infected mice displayed greater numbers of Proteobacteria and less Saccharibacteria at the phylum level and more Lactobacillaceae and Helicobacteraceae and less Prevotellaceae and Ruminococcaceae at the family level. A total of 145 fecal metabolites were found to be significantly different in prion infection, and most (114) of these were lipid metabolites. Using KEGG pathway enrichment analysis, we found that 3 phosphatidylcholine (PC) compounds significantly decreased and 4 hydrophobic bile acids significantly increased. Decreases of 8 types of short-chain acids (SCFAs) and increases of Cys and Tyr and decreases of His, Trp, and Arg were observed in prion infection. Correlation analysis indicated that the gut microbiota changes observed in our study may have been the shared outcome of prion disease. These findings suggest that prion disease can cause significant shifts in the gut microbiota. Certain bacterial taxa can then respond to the resulting change to the enteric environment by causing dramatic shifts in metabolite levels. Our data highlight the health impact of the gut microbiota and related metabolites in prion disease.

    更新日期:2019-12-17
  • Neuroprotective function of Omi to α-synuclein-induced neurotoxicity
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-16
    Hea-Jong Chung; Md. Saidul Islam; Md. Mashiar Rahman; Seong-Tshool Hong

    The main pathological hallmark of Parkinson's disease (PD) is the presence of Lewy bodies, which mainly consist of aggregated α-synuclein. Based on the neurotoxicity of oligomeric α-synuclein and its significance in the aetiology of PD, there has been decades of effort to elucidate an enzyme specifically degrading oligomeric α-synuclein. Here we report an enzyme, Omi, which specifically recognizes and precisely degrades oligomeric α-synuclein but not monomeric α-synuclein. After enzymatic and functional analyses of Omi in in vitro, we developed an in vivo assay system of dual gene interaction in Drosophila to investigate further the etiological role of Omi in PD. Pan-neuronal expression of Omi rescued Parkinsonism in a Drosophila model of PD, while Knockout of Omi exacerbated Parkinsonism. Expression of Omi counteracted the α-synuclein-induced retinal degeneration, providing additional evidence for Omi's protective role oligomeric α-synuclein. This work reports identification of the catabolic pathway of oligomeric α-synuclein as well as showing how Omi functions as the key molecule in the recognition and degradation of toxic oligomeric α-synuclein, a possible cause of neurodegeneration in PD, without affecting monomeric α-synuclein which is a native essential molecule for the normal function of neurons.

    更新日期:2019-12-17
  • Longitudinal transcriptomic analysis of altered pathways in a CHMP2Bintron5-based model of ALS-FTD
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-16
    Waegaert Robin; Dirrig-Grosch Sylvie; Parisot Florian; Keime Céline; Henriques Alexandre; Loeffler Jean-Philippe; René Frédérique
    更新日期:2019-12-17
  • Characterization of novel conformation-selective α-synuclein antibodies as potential immunotherapeutic agents for Parkinson's disease
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-16
    Michael X. Henderson; Dustin J. Covell; Charlotte Hiu-Yan Chung; Rose M. Pitkin; Raizel M. Sandler; Samantha C. Decker; Dawn M. Riddle; Bin Zhang; Ronald J. Gathagan; Michael J. James; John Q. Trojanowski; Kurt R. Brunden; Virginia M.Y. Lee; Kelvin C. Luk

    Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases for which there is no disease-modifying treatment. PD and DLB are characterized by aggregation of the synaptic protein α-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic α-synuclein through the brains of afflicted individuals. Therapies targeting extracellular, pathogenic α-synuclein may therefore hold promise for slowing or halting disease progression. In this regard, it has been suggested that highly-selective antibodies can be administered as therapeutic agents targeting pathogenic proteins. In the current study, we screened a series of antibodies using multiple selection criterion to identify those that selectively bind pathogenic α-synuclein and show potent inhibition of pathology seeding in a neuronal model of α-synucleinopathy. A lead antibody was tested in a mouse model of PD, and it was able to reduce the spread of α-synuclein pathology in the brain and attenuate dopamine reductions in the striatum. This study highlights the therapeutic potential of α-synuclein immunotherapy for the treatment of PD and DLB, and provides a framework for screening of α-synuclein antibodies to identify those with preferred properties.

    更新日期:2019-12-17
  • Knockdown of GADD34 in neonatal mutant SOD1 mice ameliorates ALS
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-16
    Ghanashyam D. Ghadge; Yoshifumi Sonobe; Adrian Camarena; Claire Drigotas; Frank Rigo; Karen K. Ling; Raymond P. Roos

    Mutations in Cu/Zn superoxide dismutase (SOD1) cause ~20% of familial ALS (FALS), which comprises 10% of total ALS cases. In mutant SOD1- (mtSOD1-) induced ALS, misfolded aggregates of SOD1 lead to activation of the unfolded protein response/integrated stress response (UPR/ISR). Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), a kinase that phosphorylates eukaryotic translation initiator factor 2α (p-eIF2α), coordinates the response by causing a global suppression of protein synthesis. Growth arrest and DNA damage 34 (GADD34) dephosphorylates p-eIF2α, allowing protein synthesis to return to normal. If the UPR/ISR is overwhelmed by the amount of misfolded protein, CCAAT/enhancer-binding homologous protein (CHOP) is activated leading to apoptosis. In the current study we investigated the effect of knocking down CHOP and GADD34 on disease of G93A and G85R mtSOD1 mice. Although a CHOP antisense oligonucleotide had no effect on survival, an intravenous injection of GADD34 shRNA encoded in adeno-associated virus 9 (AAV9) into neonatal G93A as well as neonatal G85R mtSOD1 mice led to a significantly increased survival. G85R mtSOD1 mice had a reduction in SOD1 aggregates/load, astrocytosis, and microgliosis. In contrast, there was no change in disease phenotype when GADD34 shRNA was delivered to older G93A mtSOD1 mice. Our current study shows that GADD34 shRNA is effective in ameliorating disease when administered to neonatal mtSOD1 mice. Targeting the UPR/ISR may be beneficial in mtSOD1-induced ALS as well as other neurodegenerative diseases in which misfolded proteins and ER stress have been implicated.

    更新日期:2019-12-17
  • Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-15
    Sachiko Noda; Shigeto Sato; Takahiro Fukuda; Norihiro Tada; Yasuo Uchiyama; Keiji Tanaka; Nobutaka Hattori
    更新日期:2019-12-17
  • The microbiota-immune axis as a central mediator of gut-brain communication
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-14
    Thomas C. Fung

    Intestinal inflammatory disorders are associated with neurophysiological and behavioral symptoms. Conversely, many disorders of the central nervous system (CNS) are accompanied by intestinal complications. These observations suggest that the physiologies of the intestine and nervous system are functionally linked. Indeed, a growing body of literature has revealed multiple pathways mediating bidirectional communication between the intestine and the CNS, collectively referred to as the gut-brain axis. In particular, microbes naturally colonizing the mammalian gastrointestinal (GI) tract, termed the gut microbiota, not only correlate with but play a causative role in regulating CNS function, development and behavior. Despite these findings, our understanding of the cellular and molecular mechanisms that mediate gut-brain communication remains in its infancy. However, members of the gut microbiota have been established as potent modulators of intestinal, systemic and CNS-resident immune cell function, suggesting that gut-brain interactions may involve the host immune system. Indeed, multiple CNS disorders with gut microbiota associations, including neuroinflammatory, neuropsychiatric and neurodegenerative disorders, also have significant inflammatory manifestations. In this review, I discuss recent advances exploring the role of microbiota-immune interactions as a critical regulator of the gut-brain axis in the context of CNS and related disorders.

    更新日期:2019-12-17
  • Inhibiting store-operated calcium entry attenuates white matter secondary degeneration following SCI
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-14
    Ben C. Orem; Steven B. Partain; David P. Stirling

    Axonal degeneration plays a key role in the pathogenesis of numerous neurological disorders including spinal cord injury. After the irreversible destruction of the white matter elements during the primary (mechanical) injury, spared axons and their supporting glial cells begin to breakdown causing an expansion of the lesion site. Here we mechanistically link external sources of calcium entry through axoplasmic reticulum calcium store depletion that contributes to secondary axonal degeneration through a process called store-operated calcium entry. There is increasing evidence suggesting that store-operated calcium entry impairment is responsible for numerous disorders. Nevertheless, its role following spinal cord injury remains poorly understood. We hypothesize that store-operated calcium entry mediates secondary white matter degeneration after spinal cord injury. We used our previously published model of laser-induced spinal cord injury to focally transect mid cervical dorsal column axons from live 6–8-week-old heterozygous CNPaseGFP/+: Thy1YFP+ double transgenic murine spinal cord preparations (five treated, eight controls) and documented the dynamic changes in axons over time using two-photon excitation microscopy. We report that 1 hour delayed treatment with YM-58483, a potent inhibitor of store-operated calcium entry, significantly decreased intra-axonal calcium accumulation, axonal dieback both proximal and distal to the lesion site, reduced secondary axonal “bystander” damage acutely after injury, and promoted greater oligodendrocyte survival compared to controls. We also targeted store-operated calcium entry following a clinically relevant contusion spinal cord injury model in vivo. Adult, 6–8-week-old Advillin-Cre: Ai9 mice were subjected to a mild 30 kdyn contusion and imaged to observe secondary axonal degeneration in live animals. We found that delayed treatment with YM-58483 increased axonal survival and reduced axonal spheroid formation compared to controls (n = 5 mice per group). These findings suggest that blocking store-operated calcium entry acutely is neuroprotective and introduces a novel target to prevent pathological calcium entry following spinal cord injury using a clinically relevant model.

    更新日期:2019-12-17
  • PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-14
    Kévin Duarte; Solveig Heide; Sandrine Poëa-Guyon; Véronique Rousseau; Christel Depienne; Agnès Rastetter; Caroline Nava; Tania Attié-Bitach; Ferechté Razavi; Jelena Martinovic; Marie Laure Moutard; Jacqueline Cherfils; Cyril Mignot; Delphine Héron; Jean-Vianney Barnier

    Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two “severe” G424R and K389N variants (responsible for severe ID and CCA) and the “mild” A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.

    更新日期:2019-12-17
  • Curcumin attenuates cognitive impairment by enhancing autophagy in chemotherapy
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-14
    Li-Tao Yi; Shu-Qi Dong; Shuang-Shuang Wang; Min Chen; Cheng-Fu Li; Di Geng; Ji-Xiao Zhu; Qing Liu; Jie Cheng
    更新日期:2019-12-17
  • Movement context modulates neuronal activity in motor and limbic-associative domains of the human parkinsonian subthalamic nucleus
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-14
    Odeya Marmor; Pnina Rappel; Dan Valsky; Atira S. Bick; David Arkadir; Eduard Linetzky; Or Peled; Idit Tamir; Hagai Bergman; Zvi Israel; Renana Eitan

    The subthalamic nucleus (STN), a preferred target for treating movement disorders, has a crucial role in inhibition and execution of movement. To better understand the mechanism of movement regulation in the STN of Parkinson's disease patients, we compared the same movement with different context, facilitation vs. inhibition context. We recorded subthalamic multiunit activity intra-operatively while parkinsonian patients (off medications, n = 43 patients, 173 recording sites) performed increasingly complex oddball paradigms with frequent and deviant tones: first, passive listening to tone series with no movement (‘None-Go’ task, n = 7, 28 recording sites); second, pressing a button after every tone (‘All-Go’ task, n = 7, 26 recording sites); and third, pressing a button only for frequent tones, thus adding inhibition of movement following deviant tones (‘Go-NoGo’ task, n = 29, 119 recording sites). The STN responded mainly to movement-involving tasks. In the limbic-associative STN, evoked response to the deviant tone (inhibitory cue) was not significantly different between the Go-NoGo and the All-Go task. However, the evoked response to the frequent tone (go cue) in the Go-NoGo task was significantly reduced. The reduction was mainly prominent in the negative component of the evoked response amplitude aligned to the press. Successful movement inhibition was correlated with higher baseline activity. We suggest that the STN in Parkinson's disease patients adapts to movement inhibition context by selectively decreasing the amplitude of neuronal activity. Thus, the STN enables movement inhibition not by increasing responses to the inhibitory cue but by reducing responses to the release cue. The negative component of the evoked response probably facilitates movement and a higher baseline activity enables successful inhibition of movement. These discharge modulations were found in the ventromedial, non-motor domain of the STN and therefore suggest a significant role of the limbic- associative STN domains in movement planning and in global movement regulation.

    更新日期:2019-12-17
  • Sustained neuronal and microglial alterations are associated with diverse neurobehavioral dysfunction long after experimental brain injury
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-13
    Rodney M. Ritzel; Yun Li; Junyun He; Niaz Khan; Sarah J. Doran; Alan I. Faden; Junfang Wu

    Traumatic brain injury (TBI) can cause progressive neurodegeneration, sustained neuroinflammation and chronic neurological dysfunction. Few experimental studies have explored the long-term neurobehavioral and functional cellular changes beyond several months. The present study examined the effects of a single moderate-level TBI on functional outcome 8 months after injury. Male C57BL/6 mice were subjected to controlled cortical impact injury and followed for changes in motor performance, learning and memory, as well as depressive-like and social behavior. We also used a novel flow cytometry approach to assess cellular functions in freshly isolated neurons and microglia from the injured tissue. There were marked and diverse, sustained neurobehavioral changes in injured mice. Compared to sham controls, chronic TBI mice showed long-term deficits in gait dynamics, nest building, spatial working memory and recognition memory. The tail suspension, forced swim, and sucrose consumption tests showed a marked depressive-like phenotype that was associated with impaired sociability. At the cellular level, there were lower numbers of Thy1+Tuj1+ neurons and higher numbers of activated CD45loCD11b+ microglia. Functionally, both neurons and microglia exhibited significantly higher levels of oxidative stress after injury. Microglia exhibited chronic deficits in phagocytosis of E. coli bacteria, and increased uptake of myelin and dying neurons. Living neurons showed decreased expression of synaptophysin and postsynaptic density (PSD)-95, along with greater numbers of microtubule-associated protein light chain 3 (LC3)-positive autophagosomes and increased mitochondrial mass that suggest dysregulation of autophagy. In summary, the late neurobehavioral changes found after murine TBI are similar to those found chronically after moderate-severe human head injury. Importantly, such changes are associated with microglial dysfunction and changes in neuronal activity.

    更新日期:2019-12-17
  • Activity-dependent dendritic elaboration requires Pten
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-12
    Patrick D. Skelton; Jessie Poquerusse; Julia R. Salinaro; Meijie Li; Bryan W. Luikart

    Pten, a gene associated with autism spectrum disorder, is an upstream regulator of receptor tyrosine kinase intracellular signaling pathways that mediate extracellular cues to inform cellular development and activity-dependent plasticity. We therefore hypothesized that Pten loss would interfere with activity dependent dendritic growth. We investigated the effects of this interaction on the maturation of retrovirally labeled postnatally generated wild-type and Pten knockout granule neurons in male and female mouse dentate gyrus while using chemogenetics to manipulate the activity of the perforant path afferents. We find that enhancing network activity accelerates the dendritic outgrowth of wild-type, but not Pten knockout, neurons. This was specific to immature neurons during an early developmental window. We also examined synaptic connectivity and physiological measures of neuron maturation. The input resistance, membrane capacitance, dendritic spine morphology, and frequency of spontaneous synaptic events were not differentially altered by activity in wild-type versus Pten knockout neurons. Therefore, Pten and its downstream signaling pathways regulate the activity-dependent sculpting of the dendritic arbor during neuronal maturation.

    更新日期:2019-12-13
  • Signatures of HIV-1 subtype B and C Tat proteins and their effects in the neuropathogenesis of HIV-associated neurocognitive impairments
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-11
    Monray E. Williams, Simo S. Zulu, Dan J. Stein, John A. Joska, Petrus J.W. Naudé
    更新日期:2019-12-11
  • Advances and considerations in AD tau-targeted immunotherapy
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-10
    Alice Bittar, Nemil Bhatt, Rakez Kayed

    The multifactorial and complex nature of Alzheimer's disease (AD) has made it difficult to identify therapeutic targets that are causally involved in the disease process. However, accumulating evidence from experimental and clinical studies that investigate the early disease process point towards the required role of tau in AD etiology. Importantly, a large number of studies investigate and characterize the plethora of pathological forms of tau protein involved in disease onset and propagation. Immunotherapy is one of the most clinical approaches anticipated to make a difference in the field of AD therapeutics. Tau –targeted immunotherapy is the new direction after the failure of amyloid beta (Aß)-targeted immunotherapy and the growing number of studies that highlight the Aß-independent disease process. It is now well established that immunotherapy alone will most likely be insufficient as a monotherapy. Therefore, this review discusses updates on tau-targeted immunotherapy studies, AD-relevant tau species, updates on promising biomarkers and a prospect on combination therapies to surround the disease propagation in an efficient and timely manner.

    更新日期:2019-12-11
  • Sex may influence motor phenotype in a novel rodent model of cerebral palsy
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-10
    Bhooma R. Aravamuthan, Sushma Gandham, Anne B. Young, Seward B. Rutkove
    更新日期:2019-12-11
  • Enhanced SPARCL1 expression in cancer stem cells improves preclinical modeling of glioblastoma by promoting both tumor infiltration and angiogenesis
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-10
    Filippo Gagliardi, Ashwin Narayanan, Alberto Luigi Gallotti, Valentina Pieri, Stefania Mazzoleni, Manuela Cominelli, Sara Rezzola, Michela Corsini, Gianluca Brugnara, Luisa Altabella, Letterio Salvatore Politi, Marco Bacigaluppi, Andrea Falini, Antonella Castellano, Roberto Ronca, Pietro Luigi Poliani, Pietro Mortini, Rossella Galli

    Glioblastoma (GBM) is the most malignant brain tumor of adults and is characterized by extensive cell dissemination within the brain parenchyma and enhanced angiogenesis. Effective preclinical modeling of these key features suffers from several shortcomings. Aim of this study was to determine whether modulating the expression of extracellular matrix (ECM) modifiers in proneural (PN) and mesenchymal (MES) cancer stem cells (CSCs) and in conventional glioma cell lines (GCLs) might improve tumor invasion and vascularization. To this end, we selected secreted, acidic and rich in cysteine-like 1 (SPARCL1) as a potential mediator of ECM remodeling in GBM. SPARCL1 transcript and protein expression was assessed in PN and MES CSCs as well as GCLs, in their xenografts and in patient-derived specimens by qPCR, WB and IHC. SPARCL1 expression was then enforced in both CSCs and GCLs by lentiviral-based transduction. The effect of SPARCL1 gain-of-function on microvascular proliferation, microglia activation and advanced imaging features was tested in intracranial xenografts by IHC and MRI and validated by chorioallantoic membrane (CAM) assays. SPARCL1 expression significantly enhanced the infiltrative and neoangiogenic features of PN and MES CSC/GCL-induced tumors, with the concomitant activation of inflammatory responses associated with the tumor microenvironment, thus resulting in experimental GBMs that reproduced both the parenchymal infiltration and the increased microvascular density, typical of GBM. Overall, these results indicate that SPARCL1 overexpression might be instrumental for the generation of CSC-derived preclinical models of GBM in which the main pathognomonic hallmarks of GBMs are retrievable, making them suitable for effective preclinical testing of therapeutics.

    更新日期:2019-12-11
  • Autonomic dysfunction in Parkinson’s disease: Implications for pathophysiology, diagnosis, and treatment
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-12-03
    Zhichun Chen, Guanglu Li, Jun Liu

    Parkinson’s disease (PD) is a neurodegenerative disease with a 200 year-long research history. Our understanding about its clinical phenotype and pathogenesis remains limited, although dopaminergic replacement therapy has significantly improved patient outcomes. Autonomic dysfunction is an essential category of non-motor phenotypes that has recently become a cutting edge field that directs frontier research in PD. In this review, we initially describe the epidemiology of dysautonomic symptoms in PD. Then, we perform a meticulous analysis of the pathophysiology of autonomic dysfunction in PD and propose that the peripheral autonomic nervous system may be a key route for α-synuclein pathology propagation from the periphery to the central nervous system. In addition, we recommend that constipation, orthostatic hypotension, urinary dysfunction, erectile dysfunction, and pure autonomic failure should be viewed as prodromal dysautonomic markers in PD prediction and diagnosis. Finally, we summarize the strategies currently available for the treatment of autonomic dysfunction in PD and suggest that high-quality, better-designed, randomized clinical trials should be conducted in the future.

    更新日期:2019-12-03
  • Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associated SCN1A mutation
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-28
    Yunyao Xie, Nathan N. Ng, Olga S. Safrina, Carmen M. Ramos, Kevin C. Ess, Philip H. Schwartz, Martin A. Smith, Diane K. O'Dowd

    Over 1250 mutations in SCN1A, the Nav1.1 voltage-gated sodium channel gene, are associated with seizure disorders including GEFS+. To evaluate how a specific mutation, independent of genetic background, causes seizure activity we generated two pairs of isogenic human iPSC lines by CRISPR/Cas9 gene editing. One pair is a control line from an unaffected sibling, and the mutated control carrying the GEFS+ K1270 T SCN1A mutation. The second pair is a GEFS+ patient line with the K1270 T mutation, and the corrected patient line. By comparing the electrophysiological properties in inhibitory and excitatory iPSC-derived neurons from these pairs, we found the K1270 T mutation causes cell type-specific alterations in sodium current density and evoked firing, resulting in hyperactive neural networks. We also identified differences associated with genetic background and interaction between the mutation and genetic background. Comparisons within and between dual pairs of isogenic iPSC-derived neuronal cultures provide a novel platform for evaluating cellular mechanisms underlying a disease phenotype and for developing patient-specific anti-seizure therapies.

    更新日期:2019-11-29
  • NMDA receptors on parvalbumin-positive interneurons and pyramidal neurons both contribute to MK-801 induced gamma oscillatory disturbances: Complex relationships with behaviour
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-28
    Matthew R. Hudson, Elysia Sokolenko, Terence J. O'Brien, Nigel C. Jones

    Background NMDAr antagonists induce disturbances to gamma frequency oscillations, including increasing ongoing gamma activity and reducing evoked gamma oscillations. We sought to investigate the role parvalbumin (PV+) neurons and CaMKIIα+ pyramidal cells in NMDAr antagonist-induced disturbances in gamma oscillatory activity and relate these to common behavioural consequences of these drugs by selectively deleting the obligatory GluN1 subunit from these cells in mice. Methods Adult mice (total n = 99) with GluN1 deleted from PV interneurons (PV:GluN1 KO) or CaMKIIα+ pyramidal cells (CaMKIIα:GluN1 KO), and WT littermates, were used. We assessed effects of the NMDAr antagonist MK-801 on prepulse inhibition (PPI) and locomotor behaviour. Then, mice were implanted with electrodes in the prefrontal cortex (mPFC) and hippocampus (dHPC), and the effects of MK-801 on gamma oscillations assessed. Results In WT mice, MK-801 increased ongoing gamma power, reduced evoked gamma power and increased gamma coherence. These changes were accompanied by hyperlocomotion and deficient PPI. The consequences of NMDAr antagonism were differentially regulated in the transgenic mice. The MK-801-induced increase in ongoing gamma power was significantly attenuated in both transgenic strains, but deficits to evoked gamma activity were unaffected by genotype. Deficient PPI was not affected by genotype, and only in PV:GluN1 KO mice was the hyperlocomotor phenotype of MK-801 attenuated. The emergence of abnormal gamma band hyperconnectivity between the mPFC and dHPC was absent in CaMKIIα:GluN1 KO mice. Conclusion This study suggests that the effects of NMDAr antagonism on gamma band responses and behaviour have complex relationships, and rely on different populations of neurons.

    更新日期:2019-11-29
  • Druggable genome screen identifies new regulators of the abundance and toxicity of ATXN3, the Spinocerebellar Ataxia type 3 disease protein
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-26
    Naila S. Ashraf, Joanna R. Sutton, Yemen Yang, Bedri Ranxhi, Kozeta Libohova, Emily D. Shaw, Anna J. Barget, Sokol V. Todi, Henry L. Paulson, Maria do Carmo Costa

    Spinocerebellar Ataxia type 3 (SCA3, also known as Machado-Joseph disease) is a neurodegenerative disorder caused by a CAG repeat expansion encoding an abnormally long polyglutamine (polyQ) tract in the disease protein, ataxin-3 (ATXN3). No preventive treatment is yet available for SCA3. Because SCA3 is likely caused by a toxic gain of ATXN3 function, a rational therapeutic strategy is to reduce mutant ATXN3 levels by targeting pathways that control its production or stability. Here, we sought to identify genes that modulate ATXN3 levels as potential therapeutic targets in this fatal disorder. We screened a collection of siRNAs targeting 2742 druggable human genes using a cell-based assay based on luminescence readout of polyQ-expanded ATXN3. From 317 candidate genes identified in the primary screen, 100 genes were selected for validation. Among the 33 genes confirmed in secondary assays, 15 were validated in an independent cell model as modulators of pathogenic ATXN3 protein levels. Ten of these genes were then assessed in a Drosophila model of SCA3, and one was confirmed as a key modulator of physiological ATXN3 abundance in SCA3 neuronal progenitor cells. Among the 15 genes shown to modulate ATXN3 in mammalian cells, orthologs of CHD4, FBXL3, HR and MC3R regulate mutant ATXN3-mediated toxicity in fly eyes. Further mechanistic studies of one of these genes, FBXL3, encoding a F-box protein that is a component of the SKP1-Cullin-F-box (SCF) ubiquitin ligase complex, showed that it reduces levels of normal and pathogenic ATXN3 in SCA3 neuronal progenitor cells, primarily via a SCF complex-dependent manner. Bioinformatic analysis of the 15 genes revealed a potential molecular network with connections to tumor necrosis factor-α/nuclear factor-kappa B (TNF/NF-kB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways. Overall, we identified 15 druggable genes with diverse functions to be suppressors or enhancers of pathogenic ATXN3 abundance. Among identified pathways highlighted by this screen, the FBXL3/SCF axis represents a novel molecular pathway that regulates physiological levels of ATXN3 protein.

    更新日期:2019-11-27
  • Cerebral dopamine Neurotrophic factor–deficiency leads to degeneration of enteric neurons and altered brain dopamine neuronal function in mice
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-26
    Maria Lindahl, Alcmène Chalazonitis, Erik Palm, Emmi Pakarinen, Tatiana Danilova, Tuan D. Pham, Wanda Setlik, Meenakshi Rao, Vootele Võikar, Jatta Huotari, Jaakko Kopra, Jaan-Olle Andressoo, Petteri T. Piepponen, Mikko Airavaara, Anne Panhelainen, Michael D. Gershon, Mart Saarma
    更新日期:2019-11-27
  • Galantamine protects against synaptic, axonal, and vision deficits in experimental neurotrauma
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-25
    Sarah Naguib, Alexandra Bernardo-Colón, Caroline Cencer, Neha Gandra, Tonia S. Rex

    Our goal was to investigate the neuroprotective effects of galantamine in a mouse model of blast-induced indirect traumatic optic neuropathy (bITON). Galantamine is an FDA-approved acetylcholinesterase inhibitor used to treat mild-moderate Alzheimer's disease. We exposed one eye of an anesthetized mouse to repeat bursts of over-pressurized air to induce traumatic optic neuropathy. Mice were given regular or galantamine-containing water (120 mg/L) ad libitum, beginning immediately after blast and continuing for one month. Electroretinograms and visual evoked potentials were performed just prior to endpoint collection. Histological and biochemical assessments were performed to assess activation of sterile inflammation, axon degeneration, and synaptic changes. Galantamine treatment mitigated visual function deficits induced by our bITON model via preservation of the b-wave of the electroretinogram and the N1 of the visual evoked potential. We also observed a reduction in axon degeneration in the optic nerve as well as decreased rod bipolar cell dendritic retraction. Galantamine also showed anti-inflammatory and antioxidant effects. Galantamine may be a promising treatment for blast-induced indirect traumatic optic neuropathy as well as other optic neuropathies.

    更新日期:2019-11-26
  • Tau overexpression exacerbates neuropathology after repeated mild head impacts in male mice
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-23
    Hank Cheng, Lisa M. Deaton, Minhua Qiu, Sukwon Ha, Reynand Pacoma, Jianmin Lao, Valerie Tolley, Rita Moran, Amber Keeton, John R. Lamb, John Fathman, John R. Walker, Andrew M. Schumacher

    Repeated mild traumatic brain injury (rmTBI) can lead to development of chronic traumatic encephalopathy (CTE), which is characterized by progressive neurodegeneration with presence of white matter damage, gliosis and hyper-phosphorylated tau. While animal models of rmTBI have been documented, few characterize the molecular pathogenesis and expression profiles of relevant injured brain regions. Additionally, while the usage of transgenic tau mice in rmTBI is prevalent, the effects of tau on pathological outcomes has not been well studied. Here we characterized a 42-impact closed-head rmTBI paradigm on 3–4 month old male C57BL/6 (WT) and Tau-overexpressing mice (Tau58.4). This injury paradigm resulted in chronic gliosis, T-cell infiltration, and demyelination of the optic nerve and associated white matter tracts at 1-month post-injury. At 3-months post-injury, Tau58.4 mice showed progressive neuroinflammation and neurodegeneration in multiple brain regions compared to WT mice. Corresponding to histopathology, RNAseq of the optic nerve tract at 1-month post-injury showed significant upregulation of inflammatory pathways and downregulation of myelin synthetic pathways in both genotypes. However, Tau58.4 mice showed additional changes in neurite development, protein processing, and cell stress. Comparisons with published transcriptomes of human Alzheimer's Disease and CTE revealed common signatures including neuroinflammation and downregulation of protein phosphatases. We next investigated the demyelination and T-cell infiltration phenotypes to determine whether these offer potential avenues for therapeutic intervention. Tau58.4 mice were treated with the histamine H3 receptor antagonist GSK239512 for 1-month post-injury to promote remyelination of white matter lesions. This restored myelin gene expression to sham levels but failed to repair the histopathologic lesions. Likewise, injured T-cell-deficient Rag2/Il2rg (R2G2) mice also showed evidence for inflammation and loss of myelin. However, unlike immune-competent mice, R2G2 mice had altered myeloid cell gene expression and fewer demyelinated lesions. Together this data shows that rmTBI leads to chronic white matter inflammatory demyelination and axonal loss exacerbated by human tau overexpression but suggests that immune-suppression and remyelination alone are insufficient to reverse damage.

    更新日期:2019-11-26
  • Modeling cell-autonomous motor neuron phenotypes in ALS using iPSCs
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-21
    James Hawrot, Sophie Imhof, Brian J. Wainger

    Amyotrophic lateral sclerosis (ALS) is an aggressive and uniformly fatal degenerative disease of the motor nervous system. In order to understand underlying disease mechanisms, researchers leverage a host of in vivo and in vitro models, including yeast, worms, flies, zebrafish, mice, and more recently, human induced pluripotent stem cells (iPSCs) derived from ALS patients. While mouse models have been the main workhorse of preclinical ALS research, the development of iPSCs provides a new opportunity to explore molecular phenotypes of ALS within human cells. Importantly, this technology enables modeling of both familial and sporadic ALS in the relevant human genetic backgrounds, as well as a personalized or targeted approach to therapy development. Harnessing these powerful tools requires addressing numerous challenges, including different variance components associated with iPSCs and motor neurons as well as concomitant limits of reductionist approaches. In order to overcome these obstacles, optimization of protocols and assays, confirmation of phenotype robustness at scale, and validation of findings in human tissue and genetics will cement the role for iPSC models as a valuable complement to animal models in ALS and more broadly among neurodegenerative diseases.

    更新日期:2019-11-21
  • Synaptic zinc contributes to motor and cognitive deficits in 6-hydroxydopamine mouse models of Parkinson's disease
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-20
    Joanna Sikora, Brigitte L. Kieffer, Pierre Paoletti, Abdel-Mouttalib Ouagazzal

    Hyperactivity of glutamatergic corticostrial pathways is recognized as a key pathophysiological mechanism contributing to development of PD symptoms and dopaminergic neurotoxicity. Subset of corticostriatal projection neurons uses Zn2+ as a co-transmitter alongside glutamate, but the role of synaptically released Zn2+ in PD remains unexplored. We used genetically modified mice and pharmacological tools in combination with 6-hydroxydopamine (6-OHDA) lesion models of PD to investigate the contribution of synaptic zinc to disease associated behavioral deficits and neurodegeneration. Vesicular zinc transporter-3 (ZnT3) knockout mice lacking releasable Zn2+ were more resistant to locomotor deficit and memory impairment of nigrostriatal dopamine (DA) denervation compared to wildtype littermates. The loss of striatal dopaminergic fibers was comparable between genotypes, indicating that synaptically released Zn2+ contributes to behavioral deficits but not neurotoxic effects of 6-OHDA. To gain further insight into the mechanisms of Zn2+ actions, we used the extracellular Zn2+ chelator CaEDTA and knock-in mice lacking the high affinity Zn2+ inhibition of GluN2A-containing NMDA receptors (GluN2A-NMDARs). Acute chelation of extracellular Zn2+ in the striatum restored locomotor deficit of 6-OHDA lesion, confirming that synaptic Zn2+ suppresses locomotor behavior. Disruption of the Zn2+-GluN2A interaction had, on the other hand, no impact on locomotor deficit or neurotoxic effect of 6-OHDA. Collectively, these findings provide clear evidence for the implication of striatal synaptic Zn2+ in the pathophysiology of PD. They unveil that synaptic Zn2+ plays predominantly a detrimental role by promoting motor and cognitive deficits caused by nigrostriatal DA denervation, pointing towards new therapeutic interventions.

    更新日期:2019-11-21
  • An oxygen-rich atmosphere or systemic fluoxetine extend the time to respiratory arrest in a rat model of obstructive apnea
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-20
    S. Mooney, R. Kollmar, R. Gurevich, J. Tromblee, A. Banerjee, K. Sundaram, J.B. Silverman, M. Stewart

    Audiogenic seizure-prone mice can be protected from seizure-associated death by exposure to an oxygen atmosphere or treatment with selective serotonergic reuptake inhibitors (SSRIs). We have shown previously in a rat model that epileptic seizure activity can spread through brainstem areas to cause sufficient laryngospasm for obstructive apnea and that the period of seizure-associated obstructive apnea can last long enough for respiratory arrest to occur. We hypothesized that both the oxygen-rich atmosphere and SSRIs function by prolonging the time to respiratory arrest, thus ensuring that seizure activity stops before the point of respiratory arrest to allow recovery of respiratory function. To test this hypothesis, we evaluated each preventative treatment in a rat model of controlled airway occlusion where the times to respiratory arrest can be measured. Adult male Sprague Dawley rats (median age = 66 days) were studied in the absence of any seizure activity. By directly studying responses to controlled airway occlusion, rather than airway occlusion secondary to seizure activity, we could isolate the effects of manipulations that might prolong respiratory arrest from the effects of those manipulations on seizure intensity. All group sizes were ≥ 8 animals per group. We found that both oxygen exposure and fluoxetine significantly increased the time to respiratory arrest by up to 65% (p < .0001 for 5 min oxygen exposure; p = .031 for 25 mg/kg fluoxetine tested 60 min after injection) and, given that neither treatment has been shown to significantly alter seizure duration, these increases can account for the protection of either manipulation against death in sudden death models. Importantly, we found that 30 s of exposure to oxygen produced nearly the same protection as 5 min exposure suggesting that oxygen exposure could start after a seizure starts (p = .0012 for 30 s oxygen exposure). Experiments with 50% oxygen/50% air mixtures indicate that the oxygen concentration needs to be above about 60% to ensure that times to respiratory arrest will always be longer than a period of seizure-induced airway occlusion. Selective serotonin reuptake inhibitors, while instructive with regard to mechanism, require impractical dosing and may carry additional risk in the form of greater challenges for resuscitation. We conclude that oxygen exposure or SSRI treatment prevent seizure associated death by sufficiently prolonging the time to respiratory arrest so that respiratory function can recover after the seizure abates and eliminates the stimulus for seizure-induced apnea.

    更新日期:2019-11-20
  • A randomized, double-blind, placebo-controlled trial of blue wavelength light exposure on sleep and recovery of brain structure, function, and cognition following mild traumatic brain injury
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-18
    William D.S. Killgore, John R. Vanuk, Bradley R. Shane, Mareen Weber, Sahil Bajaj

    Sleep and circadian rhythms are among the most powerful but least understood contributors to cognitive performance and brain health. Here we capitalize on the circadian resetting effect of blue-wavelength light to phase shift the sleep patterns of adult patients (aged 18–48 years) recovering from mild traumatic brain injury (mTBI), with the aim of facilitating recovery of brain structure, connectivity, and cognitive performance. During a randomized, double-blind, placebo-controlled trial of 32 adults with a recent mTBI, we compared six-weeks of daily 30-min pulses of blue light (peak λ = 469 nm) each morning versus amber placebo light (peak λ = 578 nm) on neurocognitive and neuroimaging outcomes, including gray matter volume (GMV), resting-state functional connectivity, directed connectivity using Granger causality, and white matter integrity using diffusion tensor imaging (DTI). Relative to placebo, blue light led to phase-advanced sleep timing, reduced daytime sleepiness, and improved executive functioning, and was associated with increased volume of the posterior thalamus (i.e., pulvinar), greater thalamo-cortical functional connectivity, and increased axonal integrity of these pathways. These findings provide insight into the contributions of the circadian and sleep systems in brain repair and lay the groundwork for interventions targeting the retinohypothalamic system to facilitate injury recovery.

    更新日期:2019-11-18
  • Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-11-15
    Andrea Loreto, Ciaran S. Hill, Victoria L. Hewitt, Giuseppe Orsomando, Carlo Angeletti, Jonathan Gilley, Cristiano Lucci, Alvaro Sanchez-Martinez, Alexander J. Whitworth, Laura Conforti, Federico Dajas-Bailador, Michael P. Coleman

    Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.

    更新日期:2019-11-18
  • Tetramethylenedisulfotetramine neurotoxicity: What have we learned in the past 70 years?
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-06-06
    Marcela Lauková, Jana Velíšková, Libor Velíšek, Michael P. Shakarjian

    Tetramethylenedisulfotetramine (tetramine, TETS, TMDT) is a seizure-producing neurotoxic chemical formed by the condensation of sulfamide and formaldehyde. Serendipitously discovered through an occupational exposure in 1949, it was promoted as a rodenticide but later banned worldwide due to its danger to human health. However, exceptional activity of the agent against rodent pests resulted in its clandestine manufacture with large numbers of inadvertent, intentional, and mass poisonings, which continue to this day. Facile synthesis, extreme potency, persistence, lack of odor, color, and taste identify it as an effective food adulterant and potential chemical agent of terror. No known antidote or targeted treatment is currently available. In this review we examine the origins of tetramethylenedisulfotetramine, from its identification as a neurotoxicant 70 years ago, through early research, to the most recent findings including the risk it poses in the post-911 world. Included is the information known regarding its in vitro pharmacology as a GABAA receptor channel antagonist, the toxic syndrome it produces in vivo, and its effect upon vulnerable populations. We also summarize the available information about potential therapeutic countermeasures and treatment strategies as well as the contribution of clinical development of TMDT poisoning to our understanding of epileptogenesis. Finally we identify gaps in our knowledge and suggest potentially fruitful directions for continued research on this dangerous, yet intriguing compound.

    更新日期:2019-11-18
  • Novel centrally active oxime reactivators of acetylcholinesterase inhibited by surrogates of sarin and VX
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-05-31
    Janice E. Chambers, Edward C. Meek

    A novel oxime platform, the substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937), was invented at Mississippi State University with an objective of discovering a brain-penetrating antidote to highly potent organophosphate anticholinesterases, such as the nerve agents. The goal was reactivation of inhibited brain acetylcholinesterase to attenuate the organophosphate-induced hypercholinergic activity that results in glutamate-mediated excitotoxicity and neuropathology. The currently approved oxime antidote in the US, 2-PAM, cannot do this. Using highly relevant surrogates of sarin and VX that leave acetylcholinesterase phosphylated with the same chemical moiety as their respective nerve agents, in vitro screens and in vivo tests in rats were conducted to identify the most efficacious members of this platform. The most promising novel oximes provided 24-h survival of lethal level surrogate exposure better than 2-PAM in almost all cases, and two of the oximes shortened the time to cessation of seizure-like behavior while 2-PAM did not. The most promising novel oximes attenuated neuropathology as indicated by immunohistochemical stains for both glia and neurons, while 2-PAM did not protect either glia or neurons. These results strongly suggest that these novel oximes can function within the brain to protect it, and therefore show great promise as potential future nerve agent antidotes.

    更新日期:2019-11-18
  • Hydrogen sulfide intoxication induced brain injury and methylene blue
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-05-16
    Philippe Haouzi, Takashi Sonobe, Annick Judenherc-Haouzi

    Hydrogen sulfide (H2S) remains a chemical hazard in the gas and farming industry. It is easy to manufacture from common chemicals and thus represents a potential threat for the civilian population. It is also employed as a method of suicide, for which incidence has recently increased in the US. H2S is a mitochondrial poison and exerts its toxicity through mechanisms that are thought to result from its high affinity to various metallo-proteins (such as – but not exclusively- the mitochondrial cytochrome c oxidase) and interactions with cysteine residues of proteins. Ion channels with critical implications for the cardiac and the brain functions appear to be affected very early during and following H2S exposure, an effect which is rapidly reversible during a light intoxication. However, during severe H2S intoxication, a coma, associated with a reduction in cardiac contractility, develops within minutes or even seconds leading to death by complete electro-mechanical dissociation of the heart. If the level of intoxication is milder, a rapid and spontaneous recovery of the coma occurs as soon as the exposure stops. The risk, although probably very small, of developing long-term debilitating motor or cognitive deficits is present. One of the major challenges impeding our effort to offer an effective treatment against H2S intoxication after exposure is that the pool of free/soluble H2S almost immediately disappears from the body preventing agents trapping free H2S (cobalt or ferric compounds) to play their protective role. This paper (1) presents and discusses the neurological symptoms and lesions observed in various animals models and in humans following an acute exposure to sub-lethal or lethal levels of H2S, (2) reviews the potential interest of methylene blue (MB), a potent cyclic redox dye – currently used for the treatment of methemoglobinemia – which has potential rescuing effects on the mitochondrial activity, as an antidote against sulfide intoxication.

    更新日期:2019-11-18
  • Antioxidant drug therapy as a neuroprotective countermeasure of nerve agent toxicity
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-04-25
    Jennifer N. Pearson-Smith, Manisha Patel

    The use of chemical warfare agents is an ongoing, significant threat to both civilians and military personnel worldwide. Nerve agents are by far the most formidable toxicants in terms of their lethality and toxicity. Nerve agents initiate neurotoxicity by the irreversible inhibition of acetylcholinesterase and resultant accumulation of acetylcholine in excitable tissues. The cholinergic toxidrome presents as miosis, lacrimation, diarrhea, fasciculations, seizures, respiratory arrest and coma. Current medical countermeasures can attenuate acute mortality and confer limited protection against secondary neuronal injury when given rapidly after exposure. However, there is an urgent need for the development of novel, add-on neuroprotective therapies to prevent mortality and long-term toxicity of nerve agents. Increasing evidence suggests that pathways other than direct acetylcholinesterase inhibition contribute to neurotoxicity and secondary neuronal injury. Among these, oxidative stress is emerging as a key therapeutic target for nerve agent toxicity. In this review, we discuss the rationale for targeting oxidative stress in nerve agent toxicity and highlight research investigating antioxidant therapy as a neuroprotective medical countermeasure to attenuate oxidative stress, neuroinflammation and neurodegeneration.

    更新日期:2019-11-18
  • Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-04-22
    Charles M. Thompson, John M. Gerdes, Henry F. VanBrocklin

    There is a unique in vivo interplay involving the mechanism of inactivation of acetylcholinesterase (AChE) by toxic organophosphorus (OP) compounds and the restoration of AChE activity by oxime antidotes. OP compounds form covalent adducts to this critical enzyme target and oximes are introduced to directly displace the OP from AChE. For the most part, the in vivo inactivation of AChE leading to neurotoxicity and antidote-based therapeutic reversal of this mechanism are well understood, however, these molecular-level events have not been evaluated by dynamic imaging in living systems at millimeter resolution. A deeper understanding of these critically, time-dependent mechanisms is needed to develop new countermeasures. To address this void and to help accelerate the development of new countermeasures, positron-emission tomography (PET) has been investigated as a unique opportunity to create platform technologies to directly examine the interdependent toxicokinetic/pharmacokinetic and toxicodynamic/pharmacodynamic features of OPs and oximes in real time within live animals. This review will cover two first-in-class PET tracers representing an OP and an oxime antidote, including their preparation, requisite pharmacologic investigations, mechanistic interpretations, biodistribution and imaging.

    更新日期:2019-11-18
  • Inducible nitric oxide synthase inhibitor, 1400W, mitigates DFP-induced long-term neurotoxicity in the rat model
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-03-30
    Marson Putra, Shaunik Sharma, Meghan Gage, Grace Gasser, Andy Hinojo-Perez, Ashley Olson, Adriana Gregory-Flores, Sreekanth Puttachary, Chong Wang, Vellareddy Anantharam, Thimmasettappa Thippeswamy
    更新日期:2019-11-18
  • Persistent behavior deficits, neuroinflammation, and oxidative stress in a rat model of acute organophosphate intoxication
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-03-21
    Michelle Guignet, Kiran Dhakal, Brenna M. Flannery, Brad A. Hobson, Dorota Zolkowska, Ashish Dhir, Donald A. Bruun, Shuyang Li, Abdul Wahab, Danielle J. Harvey, Jill L. Silverman, Michael A. Rogawski, Pamela J. Lein

    Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need for improved therapies. Rat models of acute intoxication with the OP, diisopropylfluorophosphate (DFP), are increasingly being used to evaluate therapeutic candidates for efficacy in mitigating the long-term neurologic effects associated with OP-induced SE. Many of these therapeutic candidates target neuroinflammation and oxidative stress because of their implication in the pathogenesis of persistent neurologic deficits associated with OP-induced SE. Critical to these efforts is the rigorous characterization of the rat DFP model with respect to outcomes associated with acute OP intoxication in humans, which include long-term electroencephalographic, neurobehavioral, and neuropathologic effects, and their temporal relationship to neuroinflammation and oxidative stress. To address these needs, we examined a range of outcomes at later times post-exposure than have previously been reported for this model. Adult male Sprague-Dawley rats were given pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), which was immediately followed by atropine sulfate (2 mg/kg, im) and pralidoxime (25 mg/kg, im). This exposure paradigm triggered robust electroencephalographic and behavioral seizures that rapidly progressed to SE lasting several hours in 90% of exposed animals. Animals that survived DFP-induced SE (~70%) exhibited spontaneous recurrent seizures and hyperreactive responses to tactile stimuli over the first 2 months post-exposure. Performance in the elevated plus maze, open field, and Pavlovian fear conditioning tests indicated that acute DFP intoxication reduced anxiety-like behavior and impaired learning and memory at 1 and 2 months post-exposure in the absence of effects on general locomotor behavior. Immunohistochemical analyses revealed significantly increased expression of biomarkers of reactive astrogliosis, microglial activation and oxidative stress in multiple brain regions at 1 and 2 months post-DFP, although there was significant spatiotemporal heterogeneity across these endpoints. Collectively, these data largely support the relevance of the rat model of acute DFP intoxication as a model for acute OP intoxication in the human, and support the hypothesis that neuroinflammation and/or oxidative stress represent potential therapeutic targets for mitigating the long-term neurologic sequelae of acute OP intoxication.

    更新日期:2019-11-18
  • The impact of indigenous microbes on Parkinson's disease
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-03-15
    Timothy Sampson

    The gastrointestinal tract is inhabited by trillions of individual microbes, representing hundreds to thousands of distinct species. These indigenous organisms are not simply spectators to host activity, but instead actively modulate critical aspects of host physiology. From digestion and the production of small molecules, to the maturation and tuning of immune responses, the gastrointestinal microbiome influences every organ system in the body. Growing experimental evidence demonstrates microbial influence on neurological function in both health and disease. Furthermore, sequencing of the intestinal microbe population reveals altered community structures in various neurological conditions. Here, we provide a perspective on the potential roles for the intestinal microbiome in modulating Parkinson's disease. While Parkinson's disease has been historically studied as a disease of the central nervous system, there is growing appreciation for the roles of both gastrointestinal function and its resident microbes within this disease state. Recent studies focused on the microbiome during Parkinson's disease may advance our understanding of disease etiology and provide perspective for previously unrecognized therapeutic avenues through modulation of intestinal microbes.

    更新日期:2019-11-18
  • Novel therapeutics for treating organophosphate-induced status epilepticus co-morbidities, based on changes in calcium homeostasis
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-03-12
    Laxmikant S. Deshpande, Robert J. DeLorenzo

    Organophosphate (OP) chemicals include pesticides such as parathion, and nerve gases such as sarin and soman and are considered major chemical threat agents. Acute OP exposure is associated with a cholinergic crisis and status epilepticus (SE). It is also known that the survivors of OP toxicity exhibit neurobehavioral deficits such as mood changes, depression, and memory impairment, and acquired epilepsy. Our research has focused on addressing the need to develop effective therapeutic agents that could be administered even after prolonged seizures and would prevent or lessen the chronic morbidity associated with OP-SE survival. We have developed rat survival models of OP pesticide metabolite paraoxon (POX) and nerve agent sarin surrogate diisopropyl fluorophosphate (DFP) induced SE that are being used to screen for medical countermeasures against an OP attack. Our research has focused on studying neuronal calcium (Ca2+) homeostatic mechanisms for identifying mechanisms and therapeutics for the expression of neurological morbidities associated with OP-SE survival. We have observed development of a “Ca2+ plateau” characterized by sustained elevations in neuronal Ca2+ levels in OP-SE surviving rats that coincided with the appearance of OP-SE chronic morbidities. These Ca2+ elevations had their origin in Ca2+ release from the intracellular stores such that blockade with antagonists like dantrolene, carisbamate, and levetiracetam lowered OP-SE mediated Ca2+ plateau and afforded significant neuroprotection. Since the Ca2+ plateau lasts for a prolonged period, our studies suggest that blocking it after the control of SE may represent a unique target for development of novel countermeasures to prevent long term Ca2+ mediated OP-SE neuropsychiatric comorbidities such as depression, anxiety, and acquired epilepsy (AE).

    更新日期:2019-11-18
  • A rat model of organophosphate-induced status epilepticus and the beneficial effects of EP2 receptor inhibition
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-02-25
    Asheebo Rojas, Thota Ganesh, Wenyi Wang, Jennifer Wang, Raymond Dingledine
    更新日期:2019-11-18
  • Targeting the glutamatergic system to counteract organophosphate poisoning: A novel therapeutic strategy
    Neurobiol. Dis. (IF 5.160) Pub Date : 2019-02-21
    Vassiliki Aroniadou-Anderjaska, Taiza H. Figueiredo, James P. Apland, Maria F. Braga
    更新日期:2019-11-18
  • Chronic stress-induced gut dysfunction exacerbates Parkinson's disease phenotype and pathology in a rotenone-induced mouse model of Parkinson's disease
    Neurobiol. Dis. (IF 5.160) Pub Date : 2018-12-21
    Hemraj B. Dodiya, Christopher B. Forsyth, Robin M. Voigt, Phillip A. Engen, Jinal Patel, Maliha Shaikh, Stefan J. Green, Ankur Naqib, Avik Roy, Jeffrey H. Kordower, Kalipada Pahan, Kathleen M. Shannon, Ali Keshavarzian

    Recent evidence provides support for involvement of the microbiota-gut-brain axis in Parkinson's disease (PD) pathogenesis. We propose that a pro-inflammatory intestinal milieu, due to intestinal hyper-permeability and/or microbial dysbiosis, initiates or exacerbates PD pathogenesis. One factor that can cause intestinal hyper-permeability and dysbiosis is chronic stress which has been shown to accelerate neuronal degeneration and motor deficits in Parkinsonism rodent models. We hypothesized that stress-induced intestinal barrier dysfunction and microbial dysbiosis lead to a pro-inflammatory milieu that exacerbates the PD phenotype in the low-dose oral rotenone PD mice model. To test this hypothesis, mice received unpredictable restraint stress (RS) for 12 weeks, and during the last six weeks mice also received a daily administration of low-dose rotenone (10 mg/kg/day) orally. The initial six weeks of RS caused significantly higher urinary cortisol, intestinal hyperpermeability, and decreased abundance of putative “anti-inflammatory” bacteria (Lactobacillus) compared to non-stressed mice. Rotenone alone (i.e., without RS) disrupted the colonic expression of the tight junction protein ZO-1, increased oxidative stress (N-tyrosine), increased myenteric plexus enteric glial cell GFAP expression and increased α-synuclein (α-syn) protein levels in the colon compared to controls. Restraint stress exacerbated these rotenone-induced changes. Specifically, RS potentiated rotenone-induced effects in the colon including: 1) intestinal hyper-permeability, 2) disruption of tight junction proteins (ZO-1, Occludin, Claudin1), 3) oxidative stress (N-tyrosine), 4) inflammation in glial cells (GFAP + enteric glia cells), 5) α-syn, 6) increased relative abundance of fecal Akkermansia (mucin-degrading Gram-negative bacteria), and 7) endotoxemia. In addition, RS promoted a number of rotenone-induced effects in the brain including: 1) reduced number of resting microglia and a higher number of dystrophic/phagocytic microglia as well as (FJ-C+) dying cells in the substantia nigra (SN), 2) increased lipopolysaccharide (LPS) reactivity in the SN, and 3) reduced dopamine (DA) and DA metabolites (DOPAC, HVA) in the striatum compared to control mice. Our findings support a model in which chronic stress-induced, gut-derived, pro-inflammatory milieu exacerbates the PD phenotype via a dysfunctional microbiota-gut-brain axis.

    更新日期:2019-11-18
  • Deciphering microbiome and neuroactive immune gene interactions in schizophrenia
    Neurobiol. Dis. (IF 5.160) Pub Date : 2018-11-22
    Emily G. Severance, Robert H. Yolken

    The body's microbiome represents an actively regulated network of novel mechanisms that potentially underlie the etiology and pathophysiology of a wide range of diseases. For complex brain disorders such as schizophrenia, understanding the cellular and molecular pathways that intersect the bidirectional gut-brain axis is anticipated to lead to new methods of treatment. The means by which the microbiome might differ across neuropsychiatric and neurological disorders are not known. Brain disorders as diverse as schizophrenia, major depression, Parkinson's disease and multiple sclerosis appear to share a common pathology of an imbalanced community of commensal microbiota, often measured in terms of a leaky gut phenotype accompanied by low level systemic inflammation. While environmental factors associated with these disease states might contribute to intestinal pathologies, products from a perturbed microbiome may also directly promote specific signs, symptoms and etiologies of individual disorders. We hypothesize that in schizophrenia, it is the putatively unique susceptibility related to genes that modulate the immune system and the gut-brain pleiotropy of these genes which leads to a particularly neuropathological response when challenged by a microbiome in dysbiosis. Consequences from exposure to this dysbiosis may occur during pre- or post-natal time periods and thus may interfere with normal neurodevelopment in those who are genetically predisposed. Here, we review the evidence from the literature which supports the idea that the intersection of the microbiome and immune gene susceptibility in schizophrenia is relevant etiologically and for disease progression. Figuring prominently at both ends of the gut-brain axis and at points in between are proteins encoded by genes found in the major histocompatibility complex (MHC), including select MHC as well as non-MHC complement pathway genes.

    更新日期:2019-11-18
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