Open Access Published by De Gruyter Open Access

Volume 4 Issue 4

December 2013

Issue of Translational Neuroscience

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Contents
Journal Overview

Open Access December 20, 2013

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

Aida Attar, Farid Rahimi, Gal Bitan

Page range: 385-409

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Abstract

Abnormal protein folding and self-assembly causes over 30 cureless human diseases for which no disease-modifying therapies are available. The common side to all these diseases is formation of aberrant toxic protein oligomers and amyloid fibrils. Both types of assemblies are drug targets, yet each presents major challenges to drug design, discovery, and development. In this review, we focus on two small molecules that inhibit formation of toxic amyloid protein assemblies — the green-tea derivative (−)-epigallocatechin-3-gallate (EGCG), which was identified through a combination of epidemiologic data and a compound library screen, and the molecular tweezer CLR01, whose inhibitory activity was discovered in our group based on rational reasoning, and subsequently confirmed experimentally. Both compounds act in a manner that is not specific to one particular protein and thus are useful against a multitude of amyloidogenic proteins, yet they act via distinct putative mechanisms. CLR01 disrupts protein aggregation through specific binding to lysine residues, whereas the mechanisms underlying the activity of EGCG are only recently beginning to unveil. We discuss current in vitro and, where available, in vivo literature related to EGCG and CLR01’s effects on amyloid β-protein, α-synuclein, transthyretin, islet amyloid polypeptide, and calcitonin. We also describe the toxicity, pharmacokinetics, and mechanism of action of each compound.

Open Access December 20, 2013

Grey and white matter brain network changes in frontotemporal dementia subtypes

Tim Nguyen, Maxime Bertoux, Claire O’Callaghan, Samrah Ahmed, John Hodges, Michael Hornberger

Page range: 410-418

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Open Access December 20, 2013

The effect of nucleus accumbens lesions on appetite, sexual function, and nicotine dependence in recovering heroin addicts

Yarong Wang, Jia Zhu, Ling Chen, Yijun Liu, Qiang Li, Weichuan Yang, Wei Li, Liyan Zhao, Mark Gold, Jifeng Sun, Wei Wang

Page range: 419-428

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Abstract

The nucleus accumbens (NAc) is a key part of the neural circuitry that creates reward, pleasure and motivation that facilitates human feeding, sexual and smoking behaviors. In the brain reward system, the NAc is a crucial component responsible for natural and drug-induced reinforcement behaviors. Yet it is unclear whether NAc is indispensible for all reward behaviors in human beings. The present study aimed to investigate the long-term effects of NAc ablation on sexual function, appetite, and nicotine dependence level in chronic heroin users. Eighteen former heroin-dependent patients (male) with bilateral NAc ablation via stereotactic radiofrequency surgery for alleviating drug psychological dependence were recruited. Their postoperative time ranged from 12 to 103 months. All subjects received MRI scans for assessing the accuracy of the lesion site. Evaluation of appetite, sexual function, and nicotine dependence were measured using the Simplified Nutrition Appetite Questionnaire, the Brief Sexual Function Inventory, and the Fagerström Test for Nicotine Dependence, respectively. After precluding the potential confounding variables, such as drug use (dosage and duration), post-operation duration, age, body-weight, marital status and education level, ANOVA with repeated measures revealed that the NAc ablation improved the patients’ appetite, sexual drive and sexual satisfaction. Yet there was no change in male erectile function, ejaculatory function, or nicotine dependence levels compared to the preoperative. These may suggest that although NAc is a key part of the neural circuitry, the NAc surgical lesions left the fundamental aspects of natural and drug-induced reinforcement and motivation almost intact.

Open Access December 20, 2013

Gabapentin is neuroprotective through glutamate receptor-independent mechanisms in staurosporine-induced apoptosis of cultured rat cerebellar neurons

Bogdan Popescu, Maria Ţuineag, Radu Stoica

Page range: 429-436

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Abstract

The anticonvulsants that are currently available modulate the activity of neuronal receptors and ion channels, which are equally involved in apoptotic pathways. We investigated the hypothesis that gabapentin (GP), an anticonvulsant without effect on glutamate receptors acting as GABA analog, has neuroprotective properties. For comparison, we chose topiramate (TPM), which has been reported to be neuroprotective via AMPA receptors blockade. For this purpose, we used rat cerebellar granule neuron (CGN) cultures and we triggered apoptosis independent of glutamate receptors with staurosporine, a broad-spectrum protein kinase inhibitor. GP at therapeutic range concentration significantly increased cell viability in CGN cultures maintained in physiological KCl concentration and reversed apoptosis induced by staurosporine. Blockade of NMDA or AMPA receptors by MK801 or NBQX, respectively, did not alter GP neuroprotection, which was reversed instead by GABA. In contrast, protective effect of TPM on STS-treated CGN cultures was annihilated by NBQX, and not altered by MK801 or GABA. Treatments with neuroprotective concentrations of GP or TPM did not modify the expression of neuronal cell adhesion molecule or synaptophysin or the morphological aspect of neuronal endings. In summary, we report that GP is neuroprotective through glutamate-receptor independent mechanisms and without alteration of neuronal plasticity markers, which makes it a possible candidate for clinical neuroprotection trials.

Open Access December 20, 2013

Social cognition in major depressive disorder: A new paradigm?

Pablo Billeke, Samantha Boardman, P. Doraiswamy

Page range: 437-447

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Abstract

Social cognition refers to the brain mechanisms by which we process social information about other humans and ourselves. Alterations in interpersonal and social functioning are common in major depressive disorder, though only poorly addressed by current pharmacotherapies. Further standardized tests, such as depression ratings or neuropsychologic tests, used in routine practice provide very little information on social skills, schemas, attributions, stereotypes and judgments related to social interactions. In this article, we review recent literature on how healthy human brains process social decisions and how these processes are altered in major depressive disorder. We especially focus on interactive paradigms (e.g., game theory based tasks) that can reproduce daily life situations in laboratory settings. The evidences we review, together with the rich literature on the protective role of social networks in handling stress, have implications for developing more ecologically-valid biomarkers and interventions in order to optimize functional recovery in depressive disorders.

Open Access December 20, 2013

Memory consolidation — Mechanisms and opportunities for enhancement

Netasha Shaikh, Elizabeth Coulthard

Page range: 448-457

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Abstract

Memory consolidation is the process by which relevant information is selected and transferred from a short-term, fragile state, into a stable, longer term domain from which it can be recalled. Effective memory underpins our ability to carry out everyday activities. When memory consolidation fails, such as in Alzheimer’s disease, the consequences can be devastating. Understanding the neurobiology of memory will help develop treatments for patients with memory loss. Here we describe the myriad processes involved in memory consolidation, including cholinergic and dopaminergic neurotransmission predominantly in hippocampal networks. We discuss established therapies as well as potential novel strategies for boosting cognition. Future approaches to enhancement of memory consolidation include not only pharmacological and neurosurgical treatments, but also lifestyle interventions — for example, modifications to sleep, exercise and diet.

Open Access December 20, 2013

Non-invasive cerebellar stimulation in dystonia

Lynton Graetz, Lynley Bradnam

Page range: 458-465

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Abstract

Primary isolated dystonia is a hyperkinetic movement disorder whereby involuntary muscle contractions cause twisted and abnormal postures. Dystonia of the cervical spine and upper limb may present as sustained muscle contractions or task-specific activity when using the hand or upper limb. There is little understanding of the pathophysiology underlying dystonia and this presents a challenge for clinicians and researchers alike. Emerging evidence that the cerebellum is involved in the pathophysiology of dystonia using network models presents the intriguing concept that the cerebellum could provide a novel target for non-invasive brain stimulation. Non-invasive stimulation to increase cerebellar excitability improved aspects of handwriting and circle drawing in a small cohort of people with focal hand and cervical dystonia. Mechanisms underlying the improvement in function are unknown, but putative pathways may involve the red nucleus and/or the cervical propriospinal system. Furthermore, recent understanding that the cerebellum has both motor and cognitive functions suggests that non-invasive cerebellar stimulation may improve both motor and non-motor aspects of dystonia. We propose a combination of motor and non-motor tasks that challenge cerebellar function may be combined with cerebellar non-invasive brain stimulation in the treatment of focal dystonia. Better understanding of how the cerebellum contributes to dystonia may be gained by using network models such as our putative circuits involving red nucleus and/or the cervical propriospinal system. Finally, novel treatment interventions encompassing both motor and non-motor functions of the cerebellum may prove effective for neurological disorders that exhibit cerebellar dysfunction.

Open Access December 20, 2013

Hyperphosphorylation of tau by GSK-3β in Alzheimer’s disease: The interaction of Aβ and sphingolipid mediators as a therapeutic target

Maja Jembrek, Mirjana Babić, Nela Pivac, Patrick Hof, Goran Šimić

Page range: 466-476

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the extracellular deposits of β amyloid peptides (Aβ) in senile plaques, and intracellular aggregates of hyperphosphorylated tau in neurofibrillary tangles (NFT). Although accumulation of Aβ has been long considered a leading hypothesis in the disease pathology, it is increasingly evident that the role hyperphosphorylation of tau in destabilization of microtubule assembly and disturbance of axonal transport is equally detrimental in the neurodegenerative process. The main kinase involved in phosphorylation of tau is glycogen-synthase kinase 3-beta (GSK-3β). Intracellular accumulation of Aβ also likely induces increase in hyperphosphorylated tau by a mechanism dependent on GSK-3β. In addition, Aβ affects production of ceramides, the major sphingolipids in mammalian cells, by acting on sphingomyelinases, enzymes responsible for the catabolic formation of ceramides from the sphingomyelin. Generated ceramides in turn increase production of Aβ by acting on β-secretase, a key enzyme in the proteolytic processing of the amyloid precursor protein (APP), altogether leading to a ceramide-Aβ-hyperphosphorylated tau cascade that ends in neuronal death. Modulators and inhibitors acting on members of this devastating cascade are considered as potential targets for AD therapy. There is still no adequate treatment for AD patients. Novel therapeutic strategies increasingly consider the combination of multiple targets and interactions among the key members of implicated molecular pathways. This review summarizes recent findings and therapeutic perspectives in the pathology and treatment of AD, with the emphasis on the interplay between hyperphosphorylated tau, amyloid β, and sphingolipid mediators.

Open Access December 20, 2013

HMGB1 suppression confers neuroprotection against stroke in diabetic rats

Dohoung Kim, In-Young Choi, Hyunduk Jang, Seung-Hoon Lee

Page range: 477-483

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Open Access December 20, 2013

Asymmetric cell division: Implications for glioma development and treatment

Kate Lewis, Claudia Petritsch

Page range: 484-503

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Abstract

Glioma is a heterogeneous disease process with differential histology and treatment response. It was previously thought that the histological features of glial tumors indicated their cell of origin. However, the discovery of continuous neuro-gliogenesis in the normal adult brain and the identification of brain tumor stem cells within glioma have led to the hypothesis that these brain tumors originate from multipotent neural stem or progenitor cells, which primarily divide asymmetrically during the postnatal period. Asymmetric cell division allows these cell types to concurrently self-renew whilst also producing cells for the differentiation pathway. It has recently been shown that increased symmetrical cell division, favoring the self-renewal pathway, leads to oligodendroglioma formation from oligodendrocyte progenitor cells. In contrast, there is some evidence that asymmetric cell division maintenance in tumor stem-like cells within astrocytoma may lead to acquisition of treatment resistance. Therefore cell division mode in normal brain stem and progenitor cells may play a role in setting tumorigenic potential and the type of tumor formed. Moreover, heterogeneous tumor cell populations and their respective cell division mode may confer differential sensitivity to therapy. This review aims to shed light on the controllers of cell division mode which may be therapeutically targeted to prevent glioma formation and improve treatment response.

Open Access December 20, 2013

Is a cultural cortical recycling hypothesis likely in relation to economic artifacts?

Sacha Bourgeois-Gironde

Page range: 504-512

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Abstract

Neuroscience of material artifacts production and handling has recently pointed to the likeliness of a cultural cortical recycling hypothesis (Stout et al., 2008). This hypothesis had been more robustly established in the case of symbolic artifacts such as letters and numbers (Dehaene and Cohen, 2007). In both cases the idea is that specific cortical maps dedicated to basic perceptual and/or motor functions were re-used at some point of relatively recent human history (within temporal scales at which anatomical evolutions of the brain cannot take place) in view of the processing of novel cultural items. Optimal functional recycling jointly facilitates and carries over constraints on the processing of these artifacts. It also presumably plays a role in their emergence and morphogenesis. I present theoretical arguments and a preliminary set of behavioral and neurobiological data that might support the speculation that the historical emergence and the typical neural processing of coins — both a material and symbolic artifact which is central for modern economic life — are explained by a similar hypothesis.

Open Access December 20, 2013

Neurocognitive deficits and diffusion MR imaging abnormalities in a case of adult-onset autosomal dominant leukodystrophy

Robert Laforce, Martin Roy, Maxime Descoteaux, Christian Berthelot, Jean-Pierre Bouchard

Page range: 513-515

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Abstract

Autosomal dominant adult-onset leukodystrophy (ADLD) is a progressive hereditary disease caused by duplication of Lamin B1 on chromosome 5q23.2. It is characterized by autonomic dysregulation, pyramidal signs, and cerebellar dysfunction. Since the first description in 1984, no authors have reported on its neurocognitive sequelae or attempted to quantify the severity of white matter changes. Herein we report a case of ADLD presenting with progressive cognitive changes leading to dementia and its associated white matter damage using diffusion MR imaging.

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