4,312 results match your criteria Neurobiology of disease[Journal]


Excitatory-inhibitory imbalance in Alzheimer's disease and therapeutic significance.

Neurobiol Dis 2019 Apr 15. Epub 2019 Apr 15.

Department of Psychiatry, McGill University, Montreal, Quebec, Canada. Electronic address:

The interplay between excitatory and inhibitory circuits underlies the brain's processes and their dysregulation has been linked to cognitive decline, psychiatric disorders and epilepsy. In patients with Alzheimer's disease (AD), an elevated occurrence of seizures has been observed in both sporadic and familial forms of the condition. Although seizure activity in AD has been mainly viewed as a result of neuronal cell loss and considered to occur in later stages, it is now becoming increasingly clear that aberrant neuronal activity may be more common in patients at earlier stages than previously thought and may trigger and contribute significantly to cognitive defects. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.04.010DOI Listing
April 2019
3 Reads

Therapeutic potential of a TrkB agonistic antibody for ischemic brain injury.

Neurobiol Dis 2019 Apr 11. Epub 2019 Apr 11.

School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China; R&D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, China. Electronic address:

The clinical trials employing neuroprotectants targeting single, early pathogenic mechanisms in stroke have so far been barely successful. We found in human postmortem stroke brains that in addition to apoptosis, necroptosis also contributed to neuronal damage. Thus, a new strategy targeting both mechanisms might be necessary. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S09699961193009
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http://dx.doi.org/10.1016/j.nbd.2019.04.009DOI Listing
April 2019
11 Reads

Ablation of the pro-inflammatory master regulator miR-155 does not mitigate neuroinflammation or neurodegeneration in a vertebrate model of Gaucher's disease.

Neurobiol Dis 2019 Apr 11;127:563-569. Epub 2019 Apr 11.

The Bateson Centre, University of Sheffield, Sheffield, UK; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK. Electronic address:

Bi-allelic mutations in the glucocerebrosidase gene (GBA1) cause Gaucher's disease, the most common human lysosomal storage disease. We previously reported a marked increase in miR-155 transcript levels and early microglial activation in a zebrafish model of Gaucher's disease (gba1). miR-155 is a master regulator of inflammation and has been implicated in a wide range of different neurodegenerative disorders. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.04.008DOI Listing
April 2019
1 Read

Sleep, oscillations, interictal discharges, and seizures in human focal epilepsy.

Neurobiol Dis 2019 Apr 11;127:545-553. Epub 2019 Apr 11.

Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Bidirectional interactions between sleep and epilepsy are known since antiquity, however only the introduction of the method of electroencephalography (EEG) in 1929 contributed to objectively investigate and further unravel these obvious clinical relationships. Despite the increasing evidence over the last century, certain aspects of epilepsy and sleep interactions are still incompletely or not well understood. This article discusses the influence of sleep on adult focal epilepsy as assessed objectively via EEG, and highlights new developments of the last decade regarding sleep microstructure and new markers of the epileptogenic zone such as high-frequency oscillations >80 Hz. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.04.007DOI Listing
April 2019
1 Read

Cardiorespiratory profiling reveals primary breathing dysfunction in Kcna1-null mice: Implications for sudden unexpected death in epilepsy.

Neurobiol Dis 2019 Apr 8;127:502-511. Epub 2019 Apr 8.

Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center Shreveport, LA 71103, USA. Electronic address:

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality, but the relative importance of underlying cardiac and respiratory mechanisms remains unclear. To illuminate the interactions between seizures, respiration, cardiac function, and sleep that contribute to SUDEP risk, here we developed a mouse epilepsy monitoring unit (EMU) to simultaneously record video, electroencephalography (EEG), electromyography (EMG), plethysmography, and electrocardiography (ECG) in a commonly used genetic model of SUDEP, the Kcna1 knockout (Kcna1) mouse. During interictal periods, Kcna1 mice exhibited an abnormal absence of post-sigh apneas and a 3-fold increase in respiratory variability. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.04.006DOI Listing
April 2019
2 Reads

An integrated transcriptomics and proteomics analysis reveals functional endocytic dysregulation caused by mutations in LRRK2.

Neurobiol Dis 2019 Apr 5;127:512-526. Epub 2019 Apr 5.

Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. Electronic address:

Background: Mutations in LRRK2 are the most common cause of autosomal dominant Parkinson's disease, and the relevance of LRRK2 to the sporadic form of the disease is becoming ever more apparent. It is therefore essential that studies are conducted to improve our understanding of the cellular role of this protein. Here we use multiple models and techniques to identify the pathways through which LRRK2 mutations may lead to the development of Parkinson's disease. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.04.005DOI Listing
April 2019
2 Reads

A Parkinson's disease gene, DJ-1, regulates anti-inflammatory roles of astrocytes through prostaglandin D synthase expression.

Neurobiol Dis 2019 Apr 4;127:482-491. Epub 2019 Apr 4.

Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Worldcup-ro 164, Suwon 16499, Republic of Korea; Department of Pharmacology, Ajou University School of Medicine, Worldcup-ro 164, Suwon 16499, Republic of Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Worldcup-ro 164, Suwon 16499, Republic of Korea; Department of Brain Science, Ajou University School of Medicine, Worldcup-ro 164, Suwon 16499, Republic of Korea. Electronic address:

Dysfunctional regulation of inflammation may contribute to the progression of neurodegenerative diseases. The results of this study revealed that DJ-1, a Parkinson's disease (PD) gene, regulated expression of prostaglandin D synthase (PTGDS) and production of prostaglandin D (PGD), by which DJ-1 enhanced anti-inflammatory function of astrocytes. In injured DJ-1 knockout (KO) brain, expression of tumor necrosis factor-alpha (TNF-α) was more increased, but that of anti-inflammatory heme oxygenase-1 (HO-1) was less increased compared with that in injured wild-type (WT) brain. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.04.003DOI Listing
April 2019
1 Read

Heritability and genetic variance of dementia with Lewy bodies.

Neurobiol Dis 2019 Apr 3;127:492-501. Epub 2019 Apr 3.

Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK. Electronic address:

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.04.004DOI Listing
April 2019
1 Read
5.078 Impact Factor

Quantitative ultrasound and apoptotic death in the neonatal primate brain.

Neurobiol Dis 2019 Apr 2;127:554-562. Epub 2019 Apr 2.

Department of Neurology, University of Wisconsin, School of Medicine, Madison, WI, USA. Electronic address:

Apoptosis is triggered in the developing mammalian brain by sedative, anesthetic or antiepileptic drugs during late gestation and early life. Whether human children are vulnerable to this toxicity mechanism remains unknown, as there are no imaging techniques to capture it. Apoptosis is characterized by distinct structural features, which affect the way damaged tissue scatters ultrasound compared to healthy tissue. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S09699961193008
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http://dx.doi.org/10.1016/j.nbd.2019.03.032DOI Listing
April 2019
5 Reads

Curcumin restores innate immune Alzheimer's disease risk gene expression to ameliorate Alzheimer pathogenesis.

Neurobiol Dis 2019 Apr 2;127:432-448. Epub 2019 Apr 2.

Departments of Neurology, Geriatric Research Education and Clinical Centerand, University of California, Los Angeles (UCLA), United States of America; Departments of Medicine, University of California, Los Angeles (UCLA), United States of America; Departments of Veterans Affairs Greater Los Angeles Healthcare System, Geriatric Research Education and Clinical Center, University of California, Los Angeles (UCLA), United States of America. Electronic address:

Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.02.015DOI Listing
April 2019
4 Reads

Inducible nitric oxide synthase inhibitor, 1400W, mitigates DFP-induced long-term neurotoxicity in the rat model.

Neurobiol Dis 2019 Mar 30. Epub 2019 Mar 30.

Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, United States. Electronic address:

Chemical nerve agents (CNA) are increasingly becoming a threat to both civilians and military personnel. CNA-induced acute effects on the nervous system have been known for some time and the long-term consequences are beginning to emerge. In this study, we used diisopropylfluorophosphate (DFP), a seizurogenic CNA to investigate the long-term impact of its acute exposure on the brain and its mitigation by an inducible nitric oxide synthase (iNOS) inhibitor, 1400W as a neuroprotectant in the rat model. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.031DOI Listing
March 2019
2 Reads
5.078 Impact Factor

A mouse model for SPG48 reveals a block of autophagic flux upon disruption of adaptor protein complex five.

Neurobiol Dis 2019 Mar 28;127:419-431. Epub 2019 Mar 28.

Institute of Human Genetics, University Hospital Jena, Friedrich-Schiller-University Jena, Jena 07747, Germany. Electronic address:

Hereditary spastic paraplegia is a spastic gait disorder that arises from degeneration of corticospinal axons. The subtype SPG48 is associated with mutations in the zeta subunit of the adaptor protein complex five (AP5). AP5 function and the pathophysiology of SPG48 are only poorly understood. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.026DOI Listing
March 2019
2 Reads
5.078 Impact Factor

Unit firing and oscillations at seizure onset in epileptic rodents.

Neurobiol Dis 2019 Mar 27;127:382-389. Epub 2019 Mar 27.

Department of Neurology, University of California, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, CA, USA; Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Electronic address:

Epileptic seizures result from a variety of pathophysiological processes, evidenced by different electrographic ictal onset patterns, as seen on direct brain recordings. The two most common electrographic patterns of focal ictal onset in patients are hypersynchronous (HYP) and low-voltage fast (LVF). Whereas LVF ictal onsets were believed to result from disinhibition; based on similarities with absence seizures, focal HYP ictal onsets were believed to result from increased synchronizing inhibition. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.027DOI Listing
March 2019
2 Reads

Fast ripple analysis in human mesial temporal lobe epilepsy suggests two different seizure-generating mechanisms.

Neurobiol Dis 2019 Mar 27;127:374-381. Epub 2019 Mar 27.

Montreal Neurological Institute and Hospital, McGill University, 3801 University Street, Montreal H3A 2B4, QC, Canada.

Objective: The distinction of hypersynchronous (HYP) and low-voltage fast (LVF) onset seizures in mesial temporal lobe epilepsy (MTLE) is well established, but classifying individual seizures and patients is often challenging. Experimental work indicates a strong association of HYP with fast ripples (250-500 Hz) and of LVF with ripples (80-250 Hz). We aimed to investigate whether analysis of high-frequency oscillations can be useful for characterizing the process of seizure generation in human MTLE patients. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.030DOI Listing
March 2019
2 Reads

New piperazine multi-effect drugs prevent neurofibrillary degeneration and amyloid deposition, and preserve memory in animal models of Alzheimer's disease.

Neurobiol Dis 2019 Mar 27. Epub 2019 Mar 27.

Univ. Lille, Inserm, CHU Lille, UMR-S1172 - JPArc - Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France. Electronic address:

Alzheimer's Disease is a devastating dementing disease involving amyloid deposits, neurofibrillary tangles, progressive and irreversible cognitive impairment. Today, only symptomatic drugs are available and therapeutic treatments, possibly acting at a multiscale level, are thus urgently needed. To that purpose, we designed multi-effects compounds by synthesizing drug candidates derived by substituting a novel N,N'-disubstituted piperazine anti-amyloid scaffold and adding acetylcholinesterase inhibition property. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.028DOI Listing
March 2019
2 Reads
5.078 Impact Factor

Upregulation of tripeptidyl-peptidase 1 by 3-hydroxy-(2,2)-dimethyl butyrate, a brain endogenous ligand of PPARα: Implications for late-infantile Batten disease therapy.

Neurobiol Dis 2019 Mar 28;127:362-373. Epub 2019 Mar 28.

Department of Neurological Sciences, Rush University Medical Center, Chicago, USA; Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, USA. Electronic address:

The late-infantile Batten disease or late-infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive lysosomal storage disorder caused by mutations in the Cln2 gene leading to deficiency of lysosomal enzyme tripeptidyl peptidase 1 (TPP1). At present, available options for this fatal disorder are enzyme replacement therapy and gene therapy, which are extensively invasive and expensive. Our study demonstrates that 3-hydroxy-(2,2)-dimethyl butyrate (HDMB), a brain endogenous molecule, is capable of stimulating TPP1 expression and activity in mouse primary astrocytes and a neuronal cell line. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.025DOI Listing
March 2019
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NitroSynapsin for the treatment of neurological manifestations of tuberous sclerosis complex in a rodent model.

Neurobiol Dis 2019 Mar 27;127:390-397. Epub 2019 Mar 27.

Scintillon Institute, San Diego, CA 92121, USA; Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA; Neuroscience Translational Center, Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address:

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also express co-morbidity with anxiety and mood disorders. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.029DOI Listing
March 2019
3 Reads

Amyloid beta-mediated KIF5A deficiency disrupts anterograde axonal mitochondrial movement.

Neurobiol Dis 2019 Mar 25;127:410-418. Epub 2019 Mar 25.

Department of Biological Sciences, The University of Texas at Dallas, 800 W. Campbell Road, Richardson, TX 75080, USA. Electronic address:

Mitochondria are crucial organelles for neurophysiology and brain mitochondrial defects constitute a characteristic of Alzheimer's disease (AD). Impaired axonal mitochondrial traffic, especially the anterograde axonal mitochondrial transport is a pronouncing mitochondrial defect that underlies synaptic failure in AD-related conditions. However, the detailed molecular mechanisms of such axonal mitochondrial abnormality have not been fully understood. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.021DOI Listing
March 2019
2 Reads

The UPR-PERK pathway is not a promising therapeutic target for mutant SOD1-induced ALS.

Neurobiol Dis 2019 Mar 26;127:527-544. Epub 2019 Mar 26.

Department of Neurology, The University of Chicago Center for Peripheral Neuropathy, The University of Chicago, Chicago, IL 60637, United States. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, characterized by motor neuron death in the brain and spinal cord. Mutations in the Cu/Zn superoxide dismutase (SOD1) gene account for ~20% of all familial ALS forms, corresponding to 1%-2% of all ALS cases. One of the suggested mechanisms by which mutant SOD1 (mtSOD1) exerts its toxic effects involves intracellular accumulation of abnormal mtSOD1 aggregates, which trigger endoplasmic reticulum (ER) stress and activate its adaptive signal transduction pathways, including the unfolded protein response (UPR). Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.024DOI Listing
March 2019
1 Read

Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARγ and insulin resistance.

Neurobiol Dis 2019 Mar 22;127:350-361. Epub 2019 Mar 22.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Physiology, Nanjing Medical University, Nanjing 211166, China. Electronic address:

Congenital generalized lipodystrophy 2 (CGL2) is characterized by loss of adipose tissue, insulin resistance and cognitive deficits and caused by mutation of BSCL2/seipin gene. Seipin deletion in mice and rats causes severe lipodystrophy, insulin resistance, and cognitive impairment. Hippocampal neurons express seipin protein. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.023DOI Listing
March 2019
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Soluble tau aggregates inhibit synaptic long-term depression and amyloid β-facilitated LTD in vivo.

Neurobiol Dis 2019 Mar 22. Epub 2019 Mar 22.

Department of Pharmacology & Therapeutics, Institute of Neuroscience, Trinity College, Dublin 2, Ireland. Electronic address:

Soluble synaptotoxic aggregates of the main pathological proteins of Alzheimer's disease, amyloid β-protein (Aß) and tau, have rapid and potent inhibitory effects on long-term potentiation (LTP). Although the promotion of synaptic weakening mechanisms, including long-term depression (LTD), is posited to mediate LTP inhibition by Aß, little is known regarding the action of exogenous tau on LTD. The present study examined the ability of different assemblies of full-length human tau to affect LTD in the dorsal hippocampus of the anaesthetized rat. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.022DOI Listing
March 2019
2 Reads

A mouse model of adult-onset multiple system atrophy.

Neurobiol Dis 2019 Mar 23;127:339-349. Epub 2019 Mar 23.

Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder clinically characterized by autonomic failure in addition to various combinations of symptoms of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Despite extensive research, the mechanisms underlying the progression of MSA remain unknown. Animal models of human diseases that recapitulate their clinical, biochemical and pathological features are indispensable for increasing our understanding of their underlying molecular mechanisms, which allows preclinical studies to be advanced. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.020DOI Listing
March 2019
2 Reads

Persistent behavior deficits, neuroinflammation, and oxidative stress in a rat model of acute organophosphate intoxication.

Neurobiol Dis 2019 Mar 21. Epub 2019 Mar 21.

Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA; MIND Institute, School of Medicine, University of California-Davis, 2825 50th Street, Sacramento, CA 95817, USA. Electronic address:

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. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S09699961193007
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http://dx.doi.org/10.1016/j.nbd.2019.03.019DOI Listing
March 2019
3 Reads

Nucleolin reorganization and nucleolar stress in Purkinje cells of mutant PCD mice.

Neurobiol Dis 2019 Mar 21;127:312-322. Epub 2019 Mar 21.

Department of Anat and Cell Biology and "Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)", University of Cantabria-IDIVAL, Santander, Spain. Electronic address:

The Purkinje cell (PC) degeneration (pcd) mouse harbors a mutation in Agtpbp1 gene that encodes for the cytosolic carboxypeptidase, CCP1. The mutation causes degeneration and death of PCs during the postnatal life, resulting in clinical and pathological manifestation of cerebellar ataxia. Monogenic biallelic damaging variants in the Agtpbp1 gene cause infantile-onset neurodegeneration and cerebellar atrophy, linking loss of functional CCP1 with human neurodegeneration. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.017DOI Listing

Neuropathological changes and cognitive deficits in rats transgenic for human mutant tau recapitulate human tauopathy.

Neurobiol Dis 2019 Mar 21;127:323-338. Epub 2019 Mar 21.

Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 2B4, Canada. Electronic address:

The assembly of tau protein into abnormal filaments and brain cell degeneration are characteristic of a number of human neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Several murine models have been generated to better understand the mechanisms contributing to tau assembly and neurodegeneration. Taking advantage of the more elaborate central nervous system and higher cognitive abilities of the rat, we generated a model expressing the longest human tau isoform (2N4R) with the P301S mutation. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.018DOI Listing

Opportunities in precision psychiatry using PET neuroimaging in psychosis.

Neurobiol Dis 2019 Mar 20. Epub 2019 Mar 20.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

With the movement toward precision medicine in healthcare, recent studies of individuals with psychosis have begun to explore positron emission tomography (PET) as a tool to test for biochemical signatures that may distinguish subtypes of psychosis that guide subtype-specific therapeutic interventions. This review presents selected PET findings that exemplify early promise in using molecular imaging to predict treatment response, provide rationale for new therapeutic targets, and monitor target engagement in biomarker-defined subtypes of psychosis. PET data, among other data types, may prove useful in the scientific pursuit of identifying precision strategies to improve clinical outcomes for individuals with psychosis. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.016DOI Listing

Multiscale recordings reveal the dynamic spatial structure of human seizures.

Neurobiol Dis 2019 Mar 18;127:303-311. Epub 2019 Mar 18.

Department of Neurology, Columbia University Medical Center, New York, NY, USA; Institute for Aging, Newcastle University, Newcastle-Upon-Tyne, UK.

The cellular activity underlying human focal seizures, and its relationship to key signatures in the EEG recordings used for therapeutic purposes, has not been well characterized despite many years of investigation both in laboratory and clinical settings. The increasing use of microelectrodes in epilepsy surgery patients has made it possible to apply principles derived from laboratory research to the problem of mapping the spatiotemporal structure of human focal seizures, and characterizing the corresponding EEG signatures. In this review, we describe results from human microelectrode studies, discuss some data interpretation pitfalls, and explain the current understanding of the key mechanisms of ictogenesis and seizure spread. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.015DOI Listing
March 2019
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Beta bursts during continuous movements accompany the velocity decrement in Parkinson's disease patients.

Neurobiol Dis 2019 Mar 18;127:462-471. Epub 2019 Mar 18.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Medical Research Council Brain Network Dynamics Unit, University of Oxford, Oxford, UK. Electronic address:

Bradykinesia is reported to correlate with subthalamic beta power (13-35 Hz) recorded at rest in Parkinson's disease (PD). Pilot studies suggest adaptive deep brain stimulation triggered by amplitude threshold crossings of beta activity defined at rest is effective. This is puzzling, given that beta is suppressed during repetitive movements when bradykinesia becomes apparent. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.013DOI Listing
March 2019
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Reciprocal modulation between amyloid precursor protein and synaptic membrane cholesterol revealed by live cell imaging.

Neurobiol Dis 2019 Mar 15;127:449-461. Epub 2019 Mar 15.

Department of Pharmacology, Vanderbilt University, United States of America; Brain Institute, Florida Atlantic University, United States of America. Electronic address:

The amyloid precursor protein (APP) has been extensively studied because of its association with Alzheimer's disease (AD). However, APP distribution across different subcellular membrane compartments and its function in neurons remains unclear. We generated an APP fusion protein with a pH-sensitive green fluorescent protein at its ectodomain and a pH-insensitive blue fluorescent protein at its cytosolic domain and used it to measure APP's distribution, subcellular trafficking, and cleavage in live neurons. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.009DOI Listing
March 2019
5.078 Impact Factor

The impact of indigenous microbes on Parkinson's disease.

Authors:
Timothy Sampson

Neurobiol Dis 2019 Mar 15. Epub 2019 Mar 15.

Department of Physiology, Emory University, Atlanta, GA 30322, United States. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.014DOI Listing
March 2019
1 Read

Hyperhomocysteinemia leads to exacerbation of ischemic brain damage: Role of GluN2A NMDA receptors.

Neurobiol Dis 2019 Mar 15;127:287-302. Epub 2019 Mar 15.

Department of Neurology, University of New Mexico Health Sciences Center, 1 University of New Mexico, Albuquerque, NM 87131, United States of America. Electronic address:

Hyperhomocysteinemia has been implicated in several neurodegenerative disorders including ischemic stroke. However, the pathological consequences of ischemic insult in individuals predisposed to hyperhomocysteinemia and the associated etiology are unknown. In this study, we evaluated the outcome of transient ischemic stroke in a rodent model of hyperhomocysteinemia, developed by subcutaneous implantation of osmotic pumps containing L-homocysteine into male Wistar rats. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.012DOI Listing
March 2019
3 Reads

PPN-DBS: A utopic vision or a realistic perspective?

Neurobiol Dis 2019 Mar 16. Epub 2019 Mar 16.

Neurocentro della Svizzere Italiana, Lugano, Switzerland.

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http://dx.doi.org/10.1016/j.nbd.2019.03.011DOI Listing

Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain.

Neurobiol Dis 2019 Mar 14;127:398-409. Epub 2019 Mar 14.

Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium; Department of Molecular Biotechnology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.

We have exploited whole brain microscopy to map the progressive deposition of hyperphosphorylated tau in intact, cleared mouse brain. We found that the three-dimensional spreading pattern of hyperphosphorylated tau in the brain of an aging Tau.P301L mouse model did not resemble that observed in AD patients. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S09699961193006
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http://dx.doi.org/10.1016/j.nbd.2019.03.010DOI Listing
March 2019
7 Reads

Regional hypometabolism in the 3xTg mouse model of Alzheimer's disease.

Neurobiol Dis 2019 Mar 14;127:264-277. Epub 2019 Mar 14.

St. Boniface Hospital Research, Canada; Dept. of Pharmacology & Therapeutics, University of Manitoba, Canada. Electronic address:

Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. Although neurofibrillary tangles and amyloid beta are classic hallmarks of AD, the earliest deficits in AD progression may be caused by unknown factors. One suspected factor has to do with brain energy metabolism. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.008DOI Listing
March 2019
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Advances in molecular and cell biology of dystonia: Focus on torsinA.

Neurobiol Dis 2019 Mar 12;127:233-241. Epub 2019 Mar 12.

Department of Neurology, the University of Pennsylvania, Philadelphia, PA, USA; Raymond G. Perelman Center for Cellular and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address:

During the last two decades, our knowledge on the genetic bases of Mendelian forms of dystonia has expanded significantly. This has translated into the generation of multiple cell and animal models to explore the neurobiological bases of this hyperkinetic movement disorder. A majority of these studies have focused on DYT1 dystonia, caused by dominant mutations in the gene encoding for the protein torsinA. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.007DOI Listing
March 2019
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Novel therapeutics for treating organophosphate-induced status epilepticus co-morbidities, based on changes in calcium homeostasis.

Neurobiol Dis 2019 Mar 12. Epub 2019 Mar 12.

Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA; Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.006DOI Listing
March 2019
8 Reads

Cytosolic glucosylceramide regulates endolysosomal function in Niemann-Pick type C disease.

Neurobiol Dis 2019 Mar 12;127:242-252. Epub 2019 Mar 12.

School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK. Electronic address:

Niemann-Pick type C disease (NPCD) is a neurodegenerative disease associated with increases in cellular cholesterol and glycolipids and most commonly caused by defective NPC1, a late endosomal protein. Using ratiometric probes we find that NPCD cells show increased endolysosomal pH. In addition U18666A, an inhibitor of NPC1, was found to increase endolysosomal pH, and the number, size and heterogeneity of endolysosomal vesicles. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.005DOI Listing
March 2019
3 Reads
5.078 Impact Factor

Revisiting the role of the innate immune complement system in ALS.

Neurobiol Dis 2019 Mar 6;127:223-232. Epub 2019 Mar 6.

School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia; University of Queensland Centre for Clinical Research, The University of Queensland, Herston, QLD 4029, Australia. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the clinical and experimental evidence for the role of the complement system in driving neuroinflammation and contributing to ALS disease progression. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S09699961193006
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http://dx.doi.org/10.1016/j.nbd.2019.03.003DOI Listing
March 2019
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Beta synchrony in the cortico-basal ganglia network during regulation of force control on and off dopamine.

Neurobiol Dis 2019 Mar 6;127:253-263. Epub 2019 Mar 6.

Medical Research Council Brain Network Dynamics Unit, University of Oxford, OX1 3TH Oxford, UK; Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, OX3 9DU Oxford, UK.

Beta power suppression in the basal ganglia is stronger during movements that require high force levels and high movement effort but it has been difficult to dissociate the two. We recorded scalp EEG and basal ganglia local field potentials in Parkinson's disease patients (11 STN, 7 GPi) ON and OFF dopaminergic medication while they performed a visually-guided force matching task using a pen on a force-sensitive graphics tablet. Force adjustments were accompanied by beta power suppression irrespective of whether the force was increased or reduced. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.004DOI Listing
March 2019
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Toward integrated understanding of salience in psychosis.

Authors:
Jun Miyata

Neurobiol Dis 2019 Mar 6. Epub 2019 Mar 6.

Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. Electronic address:

Attribution of abnormally heightened salience to daily-life stimuli is considered to underlie psychosis. Dopaminergic hyperactivity in the midbrain-striatum is thought to cause such aberrant salience attribution. A "salience network" comprising the bilateral insula and anterior cingulate cortex is related to the processing of stimulus salience. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.002DOI Listing

Systemic peptide mediated delivery of an siRNA targeting α-syn in the CNS ameliorates the neurodegenerative process in a transgenic model of Lewy body disease.

Neurobiol Dis 2019 Mar 5;127:163-177. Epub 2019 Mar 5.

Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System San Diego, CA, USA. Electronic address:

Neurodegenerative disorders of the aging population are characterized by progressive accumulation of neuronal proteins such as α-synuclein (α-syn) in Parkinson's Disease (PD) and Amyloid ß (Aß) and Tau in Alzheimer's disease (AD) for which no treatments are currently available. The ability to regulate the expression at the gene transcription level would be beneficial for reducing the accumulation of these proteins or regulating expression levels of other genes in the CNS. Short interfering RNA molecules can bind specifically to target RNAs and deliver them for degradation. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.03.001DOI Listing
March 2019
4 Reads

Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome.

Neurobiol Dis 2019 Mar 1;127:210-222. Epub 2019 Mar 1.

Instituto de Biología Molecular de Barcelona (IBMB), CSIC, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain. Electronic address:

Autism spectrum disorders are early onset neurodevelopmental disorders characterized by deficits in social communication and restricted repetitive behaviors, yet they are quite heterogeneous in terms of their genetic basis and phenotypic manifestations. Recently, de novo pathogenic mutations in DYRK1A, a chromosome 21 gene associated to neuropathological traits of Down syndrome, have been identified in patients presenting a recognizable syndrome included in the autism spectrum. These mutations produce DYRK1A kinases with partial or complete absence of the catalytic domain, or they represent missense mutations located within this domain. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.02.022DOI Listing
March 2019
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An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF Aß42 and an APOE ε4 allele.

Neurobiol Dis 2019 Feb 28;127:278-286. Epub 2019 Feb 28.

Stanford University, Department of Neurology and Neurological Sciences, 300 Pasteur Dr. Room H3144, MC 5235, Stanford, CA 94305, United States of America; Stanford University, Department of Neurosurgery, 300 Pasteur Dr. Room H3144, MC 5235, Stanford, CA 94305, United States of America. Electronic address:

Objective: Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Aβ-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Aβ-42 compared to patients with normal levels.

Methods: The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Aβ-42 determinations, and neuropsychological assessments. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.02.023DOI Listing
February 2019
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Neonatal general anesthesia causes lasting alterations in excitatory and inhibitory synaptic transmission in the ventrobasal thalamus of adolescent female rats.

Neurobiol Dis 2019 Feb 28;127:472-481. Epub 2019 Feb 28.

Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, United States of America; Neuroscience Graduate Program, University of Colorado, Anschutz Medical Campus, Aurora, United States of America. Electronic address:

Ample evidence has surfaced documenting the neurotoxic effects of various general anesthetic (GA) agents in the mammalian brain when administered at critical periods of synaptogenesis. However, little is known about how this neurotoxic insult affects persisting neuronal excitability after the initial exposure. Here we investigated synaptic activity and intrinsic excitability of the ventrobasal nucleus (VB) of the thalamus caused by neonatal GA administration. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.01.016DOI Listing
February 2019

A rat model of organophosphate-induced status epilepticus and the beneficial effects of EP2 receptor inhibition.

Neurobiol Dis 2019 Feb 25. Epub 2019 Feb 25.

Department of Pharmacology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA.

This review describes an adult rat model of status epilepticus (SE) induced by diisopropyl fluorophosphate (DFP), and the beneficial outcomes of transient inhibition of the prostaglandin-E receptor EP2 with a small molecule antagonist, delayed by 2-4 h after SE onset. Administration of six doses of the selective EP2 antagonist TG6-10-1 over a 2-3 day period accelerates functional recovery, attenuates hippocampal neurodegeneration, neuroinflammation, gliosis and blood-brain barrier leakage, and prevents long-term cognitive deficits without blocking SE itself or altering acute seizure characteristics. This work has provided important information regarding organophosphate-induced seizure related pathologies in adults and revealed the effectiveness of delayed EP2 inhibition to combat these pathologies. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S09699961193004
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http://dx.doi.org/10.1016/j.nbd.2019.02.010DOI Listing
February 2019
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Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model.

Neurobiol Dis 2019 Feb 26;127:131-141. Epub 2019 Feb 26.

Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Faculty of Medicine, Université Libre de Bruxelles, 808, route de Lennik (Bldg G), B-1070 Brussels, Belgium. Electronic address:

Impaired adult hippocampal neurogenesis has been reported as a feature of Alzheimer's disease and other tauopathies and might contribute to defects in learning and memory in these diseases. To assess the interference of tau pathology, a common key-lesion in these diseases, with adult hippocampal neurogenesis we analyzed adult neurogenesis in the hippocampal dentate gyrus in wild-type mice, Tg30 mice expressing a FTDP-17 mutant tau and the same Tg30 mice deficient for mouse tau (Tg30/tauKO). The volume of the granular layer, the number of granule cells and of neuronal precursors expressing the immature markers DCX or 3R-tau were analyzed in the dentate gyrus (DG) using unbiased stereological methods. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S09699961193005
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http://dx.doi.org/10.1016/j.nbd.2019.02.021DOI Listing
February 2019
4 Reads

Reduced disease severity following therapeutic treatment with angiotensin 1-7 in a mouse model of multiple sclerosis.

Neurobiol Dis 2019 Feb 25;127:87-100. Epub 2019 Feb 25.

Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address:

Multiple Sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by autoimmune and neurodegenerative pathologies for which there is no cure and no defined etiology. Although several, modestly effective, disease modifying drugs are available to treat MS, there are presently no treatments that offer neuroprotection and prevent clinical progression. Therapies are needed that control immune homeostasis, prevent disease progression, and stimulate regeneration in the CNS. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.02.018DOI Listing
February 2019
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Genetic suppression of IKK2/NF-κB in astrocytes inhibits neuroinflammation and reduces neuronal loss in the MPTP-Probenecid model of Parkinson's disease.

Neurobiol Dis 2019 Feb 25;127:193-209. Epub 2019 Feb 25.

Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA 80523; Program in Molecular, Cellular and Integrative Neuroscience, Colorado State University, Fort Collins, CO, USA 80523. Electronic address:

Neuroinflammatory activation of glia is considered a pathological hallmark of Parkinson's disease (PD) and is seen in both human PD patients and in animal models of PD; however, the relative contributions of these cell types, especially astrocytes, to the progression of disease is not fully understood. The transcription factor, nuclear factor kappa B (NFκB), is an important regulator of inflammatory gene expression in glia and is activated by multiple cellular stress signals through the kinase complex, IKK2. We sought to determine the role of NFκB in modulating inflammatory activation of astrocytes in a model of PD by generating a conditional knockout mouse (hGfapcre/Ikbk2) in which IKK2 is specifically deleted in astrocytes. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.02.020DOI Listing
February 2019
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Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db/db mouse model of type 2 diabetes.

Neurobiol Dis 2019 Feb 23;127:76-86. Epub 2019 Feb 23.

Department of Physiology and Center for Analgesia Research Excellence, College of Medicine, University of Kentucky Medical Center, Lexington, KY, United States of America; Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, United States of America. Electronic address:

Painful diabetic neuropathy (PDN) is a devastating neurological complication of diabetes. Methylglyoxal (MG) is a reactive metabolite whose elevation in the plasma corresponds to PDN in patients and pain-like behavior in rodent models of type 1 and type 2 diabetes. Here, we addressed the MG-related spinal mechanisms of PDN in type 2 diabetes using db/db mice, an established model of type 2 diabetes, and intrathecal injection of MG in conventional C57BL/6J mice. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.02.019DOI Listing
February 2019
2 Reads

Manipulation of microbiota reveals altered callosal myelination and white matter plasticity in a model of Huntington disease.

Neurobiol Dis 2019 Feb 23;127:65-75. Epub 2019 Feb 23.

Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 138648, Singapore; Department of Medicine, National University of Singapore, 117597, Singapore; Department of Physiology, National University of Singapore, 117597, Singapore. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.nbd.2019.02.011DOI Listing
February 2019
2 Reads