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Neurobiology of Disease

Yuan Wang, Ran Meng, Gang Liu, Catherine Cao, Fenghua Chen, Kunlin Jin, Xunming Ji, Guodong Cao
Intracranial atherosclerosis (ICAS) is a progressive pathological process that causes progressive stenosis and cerebral hypoperfusion and is a major cause of stroke occurrence and recurrence around the world. Multiple factors contribute to the development of ICAS. Angiography imaging techniques can improve the diagnosis of and the selection of appropriate treatment regimens for ICAS. Neither aggressive medication nor endovascular interventions can eradicate stroke recurrence in patients with ICAS. Non-pharmacological therapies such as remote ischemic conditioning and hypothermia are emerging...
November 12, 2018: Neurobiology of Disease
Alessandro Stefani, Laura Clara Grandi, Salvatore Galati
Low frequency deep brain stimulation (DBS) of the pedunculopontine nucleus area (PPNa) has been proposed as a novel surgical target for gait dysfunction in the late stage of Parkinson's disease (PD). Since the mid-2000s, we have shown that intrasurgical delivery of stimulation in the pontine tegmentum affects the firing activity in the subthalamic nucleus (STN), but its effect on STN oscillatory rhythms has not been studied. Neuronal oscillations detected by local field potential (LFPs) have great importance, since they express complex movement-related behavior such as locomotion...
November 10, 2018: Neurobiology of Disease
Philip M Lam, Marco I González
Epilepsy is a brain disorder characterized by a predisposition to suffer epileptic seizures. Acquired epilepsy might be the result of brain insults like head trauma, stroke, brain infection, or status epilepticus (SE) when one of these triggering injuries starts a transformative process known as epileptogenesis. There is some data to suggest that, during epileptogenesis, seizures themselves damage the brain but there is no conclusive evidence to demonstrate that spontaneous recurrent seizures themselves injure the brain...
November 10, 2018: Neurobiology of Disease
Yuri Ikeda-Matsuo, Hajime Miyata, Tomoko Mizoguchi, Eisaku Ohama, Yasuhito Naito, Satoshi Uematsu, Shizuo Akira, Yasuharu Sasaki, Mitsuo Tanabe
Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Although increased production of prostaglandin E2 (PGE2 ) has been implicated in tissue damage in several pathological settings, the role of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE2 synthesis, in dopaminergic neurodegeneration remains unclear. Here we show that mPGES-1 is up-regulated in the dopaminergic neurons of the substantia nigra of postmortem brain tissue from PD patients and in neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice...
November 10, 2018: Neurobiology of Disease
Guy Keller, Orli Binyamin, Kati Frid, Ann Saada, Ruth Gabizon
Mitochondrial malfunction is a common feature in advanced stages of neurodegenerative conditions, as is the case for the accumulation of aberrantly folded proteins, such as PrP in prion diseases. In this work, we investigated mitochondrial activity and expression of related factors vis a vis PrP accumulation at the subclinical stages of TgMHu2ME199K mice, modeling for genetic prion diseases. While these mice remain healthy until 5-6 months of age, they succumb to fatal disease at 12-14 months. We found that mitochondrial respiratory chain enzymatic activates and ATP/ROS production, were abnormally elevated in asymptomatic mice, concomitant with initial accumulation of disease related PrP...
November 10, 2018: Neurobiology of Disease
Takeshi Sakurai, Nao J Gamo
Cognitive functions including social cognition improve significantly during adolescence, the time period during which the brain typically handles a large volume of incoming information from the outside environment. Processing information and responding to environmental challenges allow the prefrontal cortex, a brain region important for cognition, to mature further and establish self-identity, social skills, and other cognitive abilities, thus helping individuals to function in society. People with vulnerable circuitries predisposed by either genetic or early environmental insults, may not be able to deal with social situations appropriately, and develop network dysfunction that may lead to the onset of schizophrenia, which often occurs during this period...
November 10, 2018: Neurobiology of Disease
Frederic Sampedro, Juan Marín-Lahoz, Saul Martínez-Horta, Javier Pagonabarraga, Jaime Kulisevsky
BACKGROUND: Cognitive decline in Parkinson's disease (PD) is a highly prevalent condition with no effective treatment. Cortical atrophy is thought to promote its development but to design optimal therapeutic approaches in this clinical setting we need to understand the physiopathological mechanisms leading to this disorder. OBJECTIVE: To characterize the impact of dopaminergic degeneration on cortical integrity in early PD. METHODS: We studied 87 recently-diagnosed PD patients and 38 healthy controls from the Parkinson's Progression Marker Initiative who underwent I123-ioflupane SPECT (DATSCAN) and T1-MRI imaging...
November 6, 2018: Neurobiology of Disease
Jérôme Lamontagne-Proulx, Isabelle St-Amour, Richard Labib, Jérémie Pilon, Hélèna L Denis, Nathalie Cloutier, Florence Roux-Dalvai, Antony T Vincent, Sarah L Mason, Anne-Claire Duchez, A Droit, Steve Lacroix, Nicolas Dupré, Mélanie Langlois, Sylvain Chouinard, Michel Panisset, Roger A Barker, Eric Boilard, Francesca Cicchetti
The production of extracellular vesicles (EV) is a ubiquitous feature of eukaryotic cells but pathological events can affect their formation and constituents. We sought to characterize the nature, profile and protein signature of EV in the plasma of Parkinson's disease (PD) patients and how they correlate to clinical measures of the disease. EVs were initially collected from cohorts of PD (n = 60; Controls, n = 37) and Huntington's disease (HD) patients (Pre-manifest, n = 11; manifest, n = 52; Controls, n = 55) - for comparative purposes in individuals with another chronic neurodegenerative condition - and exhaustively analyzed using flow cytometry, electron microscopy and proteomics...
November 5, 2018: Neurobiology of Disease
Matteo Bason, Melanie Meister-Broekema, Niels Alberts, Pascale Dijkers, Steven Bergink, Ody C M Sibon, Harm H Kampinga
Several neurodegenerative diseases like Huntington's, a polyglutamine (PolyQ) disease, are initiated by protein aggregation in neurons. Furthermore, these diseases are also associated with a multitude of responses in non-neuronal cells in the brain, in particular glial cells, like astrocytes. These non-neuronal responses have repeatedly been suggested to play a disease-modulating role, but how these may be exploited to delay the progression of neurodegeneration has remained unclear. Interestingly, one of the molecular changes that astrocytes undergo includes the upregulation of certain Heat Shock Proteins (HSPs) that are classically considered to maintain protein homeostasis, thus resulting in cell autonomous protection...
November 5, 2018: Neurobiology of Disease
Sarah Schemmert, Elena Schartmann, Dominik Honold, Christian Zafiu, Tamar Ziehm, Karl-Josef Langen, Nadim Joni Shah, Janine Kutzsche, Antje Willuweit, Dieter Willbold
Alzheimer's disease, a multifactorial incurable disorder, is mainly characterised by progressive neurodegeneration, extracellular accumulation of amyloid-β protein (Aβ), and intracellular aggregation of hyperphosphorylated tau protein. During the last years, Aβ oligomers have been claimed to be the disease causing agent. Consequently, development of compounds that are able to disrupt already existing Aβ oligomers is highly desirable. We developed d-enantiomeric peptides, consisting solely of d-enantiomeric amino acid residues, for the direct and specific elimination of toxic Aβ oligomers...
November 2, 2018: Neurobiology of Disease
Sohei Kimoto, Manabu Makinodan, Toshifumi Kishimoto
Social cognition refers to the psychological processes involved in the perception, encoding, storage, retrieval, and regulation of information about others and ourselves. This process is essential for survival and reproduction in complex social environments. Recent evidence suggests that impairments in social cognition frequently occur in schizophrenia, mainly contributing to poor functional outcomes, including the inability to engage in meaningful work and maintain satisfying interpersonal relationships. With the ambiguous definition of social cognition, the neurobiology underlying impaired social cognition remains unknown, and the effectiveness of currently available intervention strategies in schizophrenia remain limited...
November 1, 2018: Neurobiology of Disease
Luka Milosevic, Robert Gramer, Tae Hyun Kim, Musleh Algarni, Alfonso Fasano, Suneil K Kalia, Mojgan Hodaie, Andres M Lozano, Milos R Popovic, William D Hutchison
Deep brain stimulation of certain target structures within the basal ganglia is an effective therapy for the management of the motor symptoms of Parkinson's disease. However, its mechanisms, as well as the pathophysiology of Parkinson's disease, are varied and complex. The classical model of Parkinson's disease states that symptoms may arise as a result of increased neuronal activity in the basal ganglia output nuclei due to downregulated GABAergic striato-nigral/-pallidal projections. We sought to investigate the stimulation and levodopa induced effects on inhibitory synaptic plasticity in these basal ganglia output nuclei, and to determine the clinical relevance of altered plasticity with respect to patients' symptoms...
November 1, 2018: Neurobiology of Disease
Marianne Sheila, Gunaseelan Narayanan, Siming Ma, Wai Leong Tam, Josiah Chai, Lawrence W Stanton
Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of polyglutamine region in the androgen receptor. To gain insights into mechanisms of SBMA, four wild-type and five SBMA iPSC lines were differentiated to spinal motor neurons (sMNs) with high efficiency. SBMA sMNs showed neurite defects, reduced sMN survival and decreased protein synthesis levels. Microarray analysis revealed a dysregulation in various neuronal-related signalling pathways in SBMA sMNs. Strikingly, FAM135B a novel gene of unknown function, was found drastically downregulated in SBMA sMNs...
November 1, 2018: Neurobiology of Disease
Cecilia Mancini, Eriola Hoxha, Luisa Iommarini, Alessandro Brussino, Uwe Richter, Francesca Montarolo, Claudia Cagnoli, Roberta Parolisi, Diana Iulia Gondor Morosini, Valentina Nicolò, Francesca Maltecca, Luisa Muratori, Giulia Ronchi, Stefano Geuna, Francesca Arnaboldi, Elena Donetti, Elisa Giorgio, Simona Cavalieri, Eleonora Di Gregorio, Elisa Pozzi, Marta Ferrero, Evelise Riberi, Giorgio Casari, Fiorella Altruda, Emilia Turco, Giuseppe Gasparre, Brendan J Battersby, Anna Maria Porcelli, Enza Ferrero, Alfredo Brusco, Filippo Tempia
Spinocerebellar ataxia 28 is an autosomal dominant neurodegenerative disorder caused by missense mutations affecting the proteolytic domain of AFG3L2, a major component of the mitochondrial m-AAA protease. However, little is known of the underlying pathogenetic mechanisms or how to treat patients with SCA28. Currently available Afg3l2 mutant mice harbour deletions that lead to severe, early-onset neurological phenotypes that do not faithfully reproduce the late-onset and slowly progressing SCA28 phenotype. Here we describe production and detailed analysis of a new knock-in murine model harbouring an Afg3l2 allele carrying the p...
October 30, 2018: Neurobiology of Disease
Andreas Weihofen, YuTing Liu, Joseph W Arndt, Christian Huy, Chao Quan, Benjamin A Smith, Jean-Luc Baeriswyl, Nicole Cavegn, Luzia Senn, Lihe Su, Galina Marsh, Pavan Auluck, Fabio Montrasio, Roger M Nitsch, Warren D Hirst, Jesse M Cedarbaum, R Blake Pepinsky, Jan Grimm, Paul H Weinreb
Aggregation of α-synuclein (α-syn) is neuropathologically and genetically linked to Parkinson's disease (PD). Since stereotypic cell-to-cell spreading of α-syn pathology is believed to contribute to disease progression, immunotherapy with antibodies directed against α-syn is considered a promising therapeutic approach for slowing disease progression. Here we report the identification, binding characteristics, and efficacy in PD mouse models of the human-derived α-syn antibody BIIB054, which is currently under investigation in a Phase 2 clinical trial for PD...
October 28, 2018: Neurobiology of Disease
Nithi Asavapanumas, Bianca Brawek, Peter Martus, Olga Garaschuk
Besides deficits in memory and cognition, impaired visual processing is common for Alzheimer's disease (AD) patients and mouse models of AD but underlying mechanisms still remain unclear. Using in vivo Ca2+ imaging of the mouse primary visual cortex (V1) we tested whether such impairment is caused by neuronal hyperactivity, an emerging functional hallmark of AD. Profound neuronal hyperactivity was indeed found in V1 of APPSWE /PS1G384A and even of PS1G384A mice, presenting neither with plaque accumulation nor with neuroinflammation...
October 24, 2018: Neurobiology of Disease
Juan Mo, Bantong Wang, Xilin Zhu, Xiaopan Wu, Ying Liu
Proline-rich transmembrane protein 2 (PRRT2) was identified as the causative gene of paroxysmal kinesigenic choreoathetosis (PKC) as well as various other neurological diseases. However, the molecular mechanisms of how mutant PRRT2 leads to abnormal synaptic function and triggers PKC are still obscure. We generated a Prrt2 truncated mutant rat model which shows spontaneous PKC-like attacks with a relative low frequency as well as increased susceptibility to pentylenetetrazol (PTZ)-induced seizures. We demonstrate that PRRT2 is expressed on both pre- and post-synaptic membranes in the M1 cortex...
October 19, 2018: Neurobiology of Disease
Domenico Nuzzo, Sara Baldassano, Antonella Amato, Pasquale Picone, Giacoma Galizzi, Gaetano Felice Caldara, Marta Di Carlo, Flavia Mulè
Growing evidence suggests a link between obesity and neurodegeneration. The purpose of the present study was to explore the neuroprotective potential of glucagon-like peptide-2 (GLP-2) in the brain of high fat diet (HFD)-fed mice. Markers of inflammation and oxidative stress were analysed in the brains of obese mice chronically treated with [Gly2 ]-GLP-2 (teduglutide), the stable analogue of the GLP-2, and they were compared to age-matched untreated obese and lean animals. Neurodegeneration was examined by TUNEL assay...
October 19, 2018: Neurobiology of Disease
Javier González-Peñas, Javier Costas, María José Ginzo Villamayor, Bin Xu
The transcriptome profiles of the cingulate gyrus region from the postmortem brain tissues of a set of well-characterized patients with schizophrenia (SCZ) and matched controls were investigated using an integrated approach that analyzed both the alterations in transcription expression pattern and rare genetic variants in expressed genes. We demonstrated increased expression of astrocyte-related genes using spatiotemporal co-expression modules that have previously been established for developing human brain, and showed these results are independent of medication dosage...
October 19, 2018: Neurobiology of Disease
Masashi Watanave, Chiaki Hoshino, Ayumu Konno, Yumi Fukuzaki, Yasunori Matsuzaki, Tohru Ishitani, Hirokazu Hirai
Cerebellar Purkinje cells (PCs) are the sole output neurons of the cerebellar cortex, and damage to PCs results in motor deficits. Spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease), a hereditary neurodegenerative disease, is caused by an abnormal expansion of the polyglutamine tract in the causative ATXN3 protein. SCA3 affects a wide range of cells in the central nervous system, including those in the cerebellum. To unravel SCA3 pathology, we used adeno-associated virus serotype 9 (AAV9) vectors to express full-length ATXN3 with an abnormally expanded 89 polyglutamine stretch (ATXN3[Q89]) in cerebellar neurons of mature wild-type mice...
October 19, 2018: Neurobiology of Disease
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