Day 2 :
Keynote Forum
Lynn Pulliam
Professor in Residence, Chief, Microbiology (VAMC) Laboratory Medicine and Medicine Clinical Laboratory,University of California, USA
• Outstanding Women in Neuroscience Lectureship, ISNV 2009
• President, International Society for Neurovirology – 2010-2012
Keynote: The evolution of the impact of peripheral immune activation on HIV cognitive impairment
Time : 09:30-10:00
Biography:
Lynn Pulliam received her PhD from the University of San Francisco Medical School in 1983. She is a Professor of Laboratory Medicine and Medicine at the University of California, San Francisco as well as Chief of Microbiology at the San Francisco Veterans Affairs Medical Center. She is the past President of the International Society for Neurovirology and serves on several editorial boards.
Abstract:
Human immunodeficiency virus (HIV) severely impacts the immune system causing phenotypic changes in peripheral cells altering both innate and adaptive immunity. In the acute phase, HIV attacks and kills CD4+T cells, followed by monocyte/macrophage (M/Mï¦) activation and an acute-phase inflammatory response. Approximately 30% of HIV-infected individuals develop an associated dementia caused by toxic soluble factors from activated M/Mï¦ï€ . With the introduction of antiretroviral therapy (ART), most infected individuals respond to therapy with a lowering of the viral load to undetectable and reconstitution to normal immune function. However, some individuals do not return to normal immune function and their M/Mï¦ continues to be activated. This continued peripheral monocyte immune activation, now chronic, continues to be associated with cognitive impairment as well as other co-morbidities. The factors responsible for this have changed as new biomarkers for milder cognitive impairment are evolving. Since the M/Mï¦ migrates to the brain, the activation state of this immune cell is critical. New mechanisms for cell-to-cell communication have been introduced. Exosomes are lipid vesicles normally secreted by a number of cells in the plasma and tissues but are increased and altered in pathological conditions. They can transport functional nucleic acids (mRNAs, miRNAs) and proteins into recipient neural cells. Monocyte-derived exosomes can enter neural cells and contribute to neural cell dysfunction by the transfer of dysregulated miRNAs. Activated monocyte-derived exosomes may contribute to the transfer of neurotoxic cargo from M/Mï¦ï€ to resident neural cells. Alternatively, miRNAs within exosomes may be exploited as a therapeutic target to diminish neural cell activation.
Keynote Forum
Sulie Chang
Seaton Hall University , USA
Keynote: HIV infection, NeuroHIV and Use of Addicitve Substances
Time : 10:00-10:30 am
Biography:
rnDr. Sulie L. Chang is the Director of the Institute of Neuroimmune Pharmacology and a Professor of Biological Sciences and Neuroscience at Seton Hall University in New Jersey. rnDr. Chang’s research is to sudy the interactions between various addictive substances including alcohol, morphine, as neuroHIV, and behavioral disorders caused by substance abuse, with the central hypothesis that neuroinflammation promotes substance abuse. Dr. Chang has been continuously funded by NIH since 1989. She has published over 100 articles in refereed journals with significant impact. Dr. Chang’s services to the scientific community include participation as a reviewer on more than 110 NIH Study Sections including as a member [2010-2014] and the Chairperson [2012-2014 of the Innate Immunity and Inflammation (III) Study Section. Dr. Chang has served on several editorial boards including the Journal of Neurovirology and Journal of Neuroimmune Pharmacology. rn
Abstract:
Abuse of addictive substances, including morphine, methamphetamine, and alcohol, is a key co-morbidity in human immunodeficiency virus-1 (HIV-1) infection. Use of various addictive substances hastens the progression of HIV-1 infection and HIV-associated neurocognitive disorders. Even with combination active anti-retroviral therapy (cART), HIV-1 viral proteins are still expressed in the body and eradication of the virus, particularly in the brain, the key reservoir organ, does not occur. Thus, the clinical challenge in the treatment of HIV infection is inflammation of the CNS and the subsequent neurological disorders. HIV-1-infected individuals reportedly use addictive substances more than the general public. There has recently been a shift from studying the detrimental impact of additive substances on HIV infection to investigation of whether HIV infection can lead to substance abuse. The HIV-1 transgenic (HIV-1Tg) rat mimiks HIV patients given cART. Even in the absence of infection, the presence of viral proteins in the HIV-1Tg rat causes immune deficiencies, neuroinflammation, and neurocognitive deficits similar to those seen in HIV-1-infected humans, such as a decline in cognitive abilities and decreased behavioral flexibility. We have demonstrated that HIV-1Tg rats are more prone to both behavioral sensitization and acute physiological effects (hyperthermia) of methamphetamine; they exhibit an increased sensitivity to morphine’s anti-nociceptive properties; and they have an increased sensitivity to the effects of binge consumption of ethanol. These studies suggest that HIV-1-induced neurological deficits and alterations in behavior associated with substance abuse and addiction may be a result of viral protein-induced neuroinflammation (partially supported by DA036175 and AA023172).
- Neuroimmunogenetics
Psychoneuroimmunology
Stem Cells for Neurological Disorder Treatments
Neuropharmacology and Therapeutics
Biomarkers in Neurodegeneration
Future Aspects
Session Introduction
E Alfonso Romero-Sandoval
Presbyterian College School of Pharmacy, USA
Title: Activating the endocannabinoid system to prevent the development of chronic pain
Time : 10:45-11:45
Biography:
E. Alfonso Romero-Sandoval is originally from Guatemala, and received his MD from Universidad de San Carlos de Guatemala in 1999 and his PhD in Neuroscience from Universidad de Alcalá, Alcalá de Henares, Spain, in 2003. He did a postdoctoral training at Wake Forest University, Winston Salem, NC (2003-2006) and at Geisel Dartmouth Medical School, Lebanon, NH (2006-2007). He was Instructor (2007-2009) and Assistant Professor (2009-2012) at Geisel Dartmouth Medical School, Lebanon, NH. Currently (2012-present) he is Associate Professor and Director of Research at Presbyterian College School of Pharmacy, Clinton, SC. Romero- Sandoval is studying the molecular mechanisms of spinal cannabinoid receptor 2 activation for induction of analgesia, the role of endocannabinoids in postoperative pain, the function of phosphatases and kinases in spinal cord in the transition from acute to chronic pain, the use of nanotechnology to promote surgical wound healing and to prevent the development of chronic postoperative pain.
Abstract:
Up to 50% of patients develop persistent or chronic pain following major surgical procedures, but the mechanisms underlying the transition from acute to chronic pain states are not fully understood. Th e endocannabinoid (ECBs) act through cannabinoid receptors type 1 (CB1) and type 2 (CB2). CB2 receptor activation in the spinal cordresult in a reduction of pain related behaviorsin a model of postoperative pain through the modulation of neuroimmune interactions via microglia and astrocytites. We then uncovered that the integrity of the endocannabinoid system is pivotal to restore a homeostatic interaction between glial cells and neurons, which results in a normal resolution of acute postoperative pain. We have demonstrated that a disruption of the endocannabinoid system results in an altered neuroimmune interaction mediated by the MAP kinase p-p38 in glial cells. Th is lecture will discuss the clinical translation value of potential therapeutics to modulate glial responses in the central nervous system as a novel strategy to prevent or treat chronic pain or other neurological conditions. A review of currentclinical scientific evidence on glial modulator drugs will close the lecture.
Pietro Paolo Sanna
Neurobiology of Addictive Disorders, Scripps Research Institute, USA
Title: Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats
Time : 11:45-12:05
Biography:
Pietro Sanna is associate professor at Department of Molecular and Cellular Neuroscience Scripps Research Institute, USA
Abstract:
Background: A thorough investigation of the neurobiology of HIV-induced neuronal dysfunction and its evolving phenotype in the setting of viral suppression has been limited by the lack of validated small animal models to probe the effects of concomitant low level expression of multiple HIV-1 products in disease-relevant cells in the CNS. Results: We report the results of gene expression profiling of the hippocampus of HIV-1 Tg rats, a rodent model of HIV infection in which multiple HIV-1 proteins are expressed under the control of the viral LTR promoter in disease-relevant cells including microglia and astrocytes. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analysis. Gene expression changes observed are consistent with astrogliosis and microgliosis and include evidence of inflammation and cell proliferation. Among the genes with increased expression in HIV-1 Tg rats was the interferon stimulated gene 15 (ISG-15), which was previously shown to be increased in the cerebrospinal fluid (CSF) of HIV patients and to correlate with neuropsychological impairment and neuropathology, and prostaglandin D2 (PGD2) synthase (Ptgds), which has been associated with immune activation and the induction of astrogliosis and microgliosis. GSEA-based pathway analysis highlighted a broad dysregulation of genes involved in neuronal trophism and neurodegenerative disorders. Among the latter are genesets associated with Huntington’s disease, Parkinson’s disease, mitochondrial, peroxisome function, and synaptic trophism and plasticity, such as IGF, ErbB and netrin signaling and the PI3K signal transduction pathway, a mediator of neural plasticity and of a vast array of trophic signals. Additionally, gene expression analyses also show altered lipid metabolism and peroxisomes dysfunction. Supporting the functional significance of these gene expression alterations, HIV-1 Tg rats showed working memory impairments in spontaneous alternation behavior in the T-Maze, a paradigm sensitive to prefrontal cortex and hippocampal function. Comparison of gene expression of the hippocampus of HIV-1 Tg rats with the National NeuroAIDS Tissue Consortium (NNTC) human HIV gene expression dataset showed largely consistent results including changes in in genes related to neuronal trophism and degeneration. Conclusions: Altogether, differentially regulated genes and pathway analysis identify specific pathways that can be targeted therapeutically to increase trophic support, e.g. IGF, ErbB and netrin signaling, and reduce neuroinflammation, e.g. PGD2 synthesis, which may be beneficial in the treatment of chronic forms of HIV-associated neurocognitive disorders in the setting of viral suppression.
Pierluigi Navarra
Catholic University Medical School, Italy
Title: Microglia polarization: A common paradigm spanning from neuro-oncology to infectious diseases
Time : 12:05-12:25
Biography:
Pierluigi Navarra is full Professor of Pharmacology at the Catholic University Medical School in Rome. He has published more than 180 full papers listed in PubMed.
Abstract:
We have investigated microglia polarization in the framework of microglia interactions with primary brain tumors. In a series of in vitro experiments, we have characterized the influence of glioma-soluble factors on microglial function, comparing the effects of media harvested under basal conditions with those of media obtained after inducing a pro-inflammatory activation state in glioma cells. Microglia exposed to basal glioma-derived factors (a condition resembling the early stage of pathology), shows increased M2b polarization status and up-regulation of IL-10 only. At variance, when exposed to activated glioma-derived factors (a condition mimicking the late stage of pathology), microglia presents as a mixture of polarization phenotypes (M1 and M2a/b), with up-regulation of iNOS, arginase and IL-10. In this paradigm, the inhibition of mTOR shifts polarization of glioma-activated microglial cells towards the M1 phenotype, thus preventing the induction of a M2 status that would promote tumor growth. Investigations are currently underway on 54 surgical specimens of glioblastoma multiforme to confirm the influence of brain tumors on microglia polarization. An apparently unrelated line of research in our lab was addressed to investigate the effects of antiretroviral drugs exposure on microglia cultures, seeking for putative mechanisms of neurotoxicity. We found that certain NNRTIs and PIs increased NO production thorough a mechanism independent from iNOS induction. Rather, these agents increased the availability of the iNOS substrate L-arginine by blocking arginase, a well-established marker of M2 polarization. Thus, the investigation of microglia polarization markers turns out to be a common background linking studies on the most different patho-physiological conditions involving the CNS.
Cintia Roodveldt
University of Seville, Spain
Title: Vaccination with heat-shock protein-chaperoned ï¡-synuclein as a novel immunotherapeutic strategy against Parkinsons Disease
Time : 12:25-12:45
Biography:
Cintia Roodveldt completed her PhD in 2005 at the Weizmann Institute of Science (Rehovot, Israel) and performed a postdoc in amyloid protein studies in 2006-2009 at the University of Cambridge, UK (Prof. Chris M. Dobson). She was a FEBS Long-Term Research Fellow, and was honored with the Clare Hall Research Fellowship (Cambridge, UK) in 2007 and with the FEBS Distinguished Young Investigator Award 2010. Since 2011 she has been leading a research group focusing on ‘immunothearapeutic approaches for neurodegenerative diseases’ at CABIMER Center (Seville, Spain). She has published her work in reputed journals as high-impact articles (holding >65 citations/article av.).
Abstract:
ï¡-synuclein (ï¡Syn) is an amyloid-forming protein whose aggregation is linked to Parkinson’s disease (PD), a ‘misfolding’ neurodegenerative disorder. ï¡Synï€ has also been found to play a critical role in the immune imbalance accompanying disease progression, a feature that has prompted research on the immunological role of ï¡Syn in PD as well as the search for an effective ï¡Syn-based immunotherapy. In this work, we investigated a novel approach that simultaneously exploits two important features of certain heat-shock proteins (HSPs): their classical ‘chaperone’ activities and their recently discovered and diverse ‘immunoactive’ properties. In particular, we have characterized the immune response elicited by immunization of naïve C57BL/6 mice with a ï¡Syn/HSP protein combination. Our results show specific differences in mice immunized with the ï¡Syn/HSP complex when compared to controls, including their Treg (CD4+CD25+Foxp3+) and Teff (CD4+Foxp3-) cell contents, altered antigen-specific response of isolated splenocytes, and different anti-ï¡Syn antibody levels in blood. Moreover, the measured serum levels of IFN-ï§ and IL-10 cytokines indicated a unique shift towards a Th2 immunomodulatory/ immunoprotective phenotype in mice immunized with ï¡Syn/HSP. Finally, we have tested the therapeutic potential of the ï¡Syn/HSP vaccine in a 1.methyl-4.phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD mouse model, showing improvements of PD symptoms in treated mice, according to standard behavioral tests (e.g. limb stride variation, rearing). Overall, we propose the use of functional ‘HSP-chaperoned amyloid/aggregating proteins’ generated with appropriate HSP-client protein combinations, such as the ï¡Syn/HSP complex used in this study, as a novel strategy for immune-based intervention against synucleinopathies and other amyloid or ‘misfolding’ neurodegenerative disorders.
Juan Pablo de Rivero Vaccari
University of Miami Miller School of Medicine, USA
Title: Targeting the innate immune response to improve outcomes after CNS injury
Time : 13:45-14:05
Biography:
Juan Pablo de Rivero Vaccari obtained his PhD in 2007 from the University of Miami for his work on therapeutically targeting the infl ammasome to improve outcomes after spinal cord injury. He then continued his studies on innate immune responses after brain trauma as a Post-doctoral fellow at the Miami Project to Cure Paralysis.He became a Research Assistant Professor in the Department of Neurological Surgery at the University of Miami in 2010. Currently, he works on identifying biomarkers and therapeutic targets in the innate immune response to improve outcomes after central nervous system injury and disease.
Abstract:
The innate immune response is the first line against infections and damage. Pattern recognition receptors (PRRs) are components of the innate immune response that recognize danger/damage associated molecular patterns (DAMPs) or pathogen associated molecular patterns (PAMPs). Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs) and C-type lectin receptors (CLRs) are PRRs involved in the recognition of DAMPs/PAMPs that trigger an infl ammatory response. NLRs form infl ammasomes that trigger the activation of caspase-1 and the processing of IL-1ï¢. RIG-I is a RLR involved in the production of type-I interferons, and mincle is a CLR involved in the production of tumor necrosis factor (TNF). Following central nervous system (CNS) injury, such as spinal cord injury (SCI), traumatic brain injury (TBI) or stroke, the inflammasome, RIG-I or mincle are activated as part of the infl ammatory response. Th erefore, these PRRs can be therapeutically targeted to control the inflammatory response in order to improve outcomes aft er SCI, TBI or stroke. For instance, delivery of an antibody against apoptosis associated speck-like protein containing a CARD (ASC), an infl ammasome component, results in decreased inflammation as well as improved histopathological and functional outcomes aft er cervical contusive SCI in a clinically relevant model in rodents. Similarly, anti-mincle can be used to inhibit TNF production in neurons in culture following stimulation with SAP130. Taken together, our fi ndings indicate that targeting PRRs can be a successful option that can be used to treat the innate immune response aft er SCI, TBI or stroke.
Jing Shang
China Pharmaceutical University, China
Title: The pathogenetic analysis of HPA axis regulated skin disorders-new inspiration on related drug development
Time : 14:05-14:25
Biography:
Jing Shang is currently working at China Pharmaceutical University, China, his reaserch interest is drug development, Neuroimmunology.
Abstract:
Skin disease belongs to a complex disease, such as vitiligo, psoriasis, alopecia areata, atopic dermatitis, etc. Its specific mechanism is so far unclear. There is a great difficulty in treatment, enough to cause much pain to the patient. Skin is as the largest organ of the human body. Its existence is not just for the body barrier to the outside threatened homeostasis, and the skin and its accessories are widely innervated, the sensory nerve in the skin is directly upward to the cerebral cortex. Th e skin can be independent to synthesize and secret the stress hormones to maintain local and systemic homeostasis, and is also one of the biggest target organs of these hormones. Taken together, the skin is as the body’s largest neuro endocrine and immune organs. Clinical survey found that the onset and development of many skin diseases were closely related to mental factors. A variety of skin diseases are contributed to the liability under psychological stress, such as urticant, atopic dermatitis, urticaria, psoriasis, acne, hair loss, etc. Mental stress can induce or aggravate the skin disorders. Psychological soothing and keeping a good state of mind can both help to alleviate these diseases. Now, for the pathogenesis analysis of these diseases, a preliminary study suggests that these skin diseases including psoriasis, vitiligo, alopecia areata, atopic dermatitis, etc., indeed have associations with mental stress. When the body responds to mental stress, the skin will present a corresponding change, such as hot fl ashes, sweating, etc. In addition to these visible external reactions, we also found that the skin showed signifi cantly increased immune cells and mast cell degranulation. Large number of experimental and clinical studies proved that mental stress involved in the development and progression of many skin diseases. In response to mental stress, the body starts the hypothalamus-pituitary-adrenal (HPA) axis to combat stress conditions. Meanwhile, skin has its own HPA axis to respond to external stress and regulate skin function such as melanogenesis. Therefore, there is a problem that how HPA axis mediates the eff ect of mental stress on skin function, so as to promote the occurrence and development of skin diseases. To study the skin’s response in face of mental stress and to explore the etiology and pathogenesis of skin diseases related to mental factors, it is of great signifi cance and importance to the exploration of treatment targets and methods involved in skin disease. This topic aims to study on the role of HPA axis in mental stress aff ecting skin functions, and investigate the mechanism of natural medicine HZCZ for regulating skin functions in a multi-target manner. This study provides a new idea of drug development for complex disease.
Carlos Fernando Mello
Federal University of Santa Maria, Brazil
Title: CysLT and EP receptors as targets for antiseizure drugs: preclinical data
Time : 14:25-14:45
Biography:
Carlos Fernando Mello has completed his MD at the age of 23 years and PhD at the age of 30 years, both from the Federal University of Rio Grande do Sul, and postdoctoral studies from University of Kentucky. He is a full professor of medical pharmacology at the Federal University of Santa Maria and has published more than a 130 papers in reputed journals and has been serving as an editorial board member of Medicine.
Abstract:
Accumulating circumstantial and experimental evidence support a role for arachidonic acid-derived inflammatory mediators in seizures. Accordingly, seizures induced by different chemoconvulsants are accompanied by time-dependent increase of leukotriene and prostaglandin synthesis. In addition, while 5-LOX and COX-2 inhibitors reduce, leukotrienes and prostaglandins, particularly PGE2, facilitate seizures, suggesting that these arachidonic acid metabolites play a role in seizure generation. Since seizure-related leukotriene and prostaglandin syntheses generate superoxide anion and selected antioxidants may decrease seizures, a number of studies have proposed that 5-LOX and COX-derived superoxide might play a major role in seizure generation and/or propagation. Moreover, since COX-2 is also involved in the metabolism of endocannabinoids, it has been suggested that COX-2 inhibition may decrease seizures by facilitating endocannabinoid-mediated inhibitory transmission. A definitive role for prostaglandins and leukotrienes, by themselves, in seizure facilitation was strengthened when it was shown that anti-PGE2 antibodies and CysLT1, EP1 and EP3 receptor antagonists decrease seizures. The reports that EP2 and DP1 receptor agonists decrease seizures constituted further evidence that the role of prostaglandin in seizure development is complex and that drug targeting shall consider the multiplicity of effects of a single prostaglandin, such as PGE2, but also the effects of the other metabolites of arachidonic acid, such as leukotrienes and PGD2. While current data suggests that EP1 and EP3 receptors may be interesting targets for novel anticonvulsants, the current availability and use of safe CysLT1 antagonists in the clinics may be a fast track for developing novel anti-seizure drugs, based on an anti-inflammatory rationale.
Ahmad Bassiouny
Alexandria University, Egypt
Title: Neuroprotective role of Curcumin and Resveratrol combination against AlCl3 induced Alzheimers disease in rats
Time : 14:45-15:05
Biography:
Ahmad Bassiouny is currently working at Alexandria University, Egypt.
Abstract:
Clinical and experimental studies have demonstrated that chronic exposure of Aluminum, proposed as an environmental factor, may affect several enzymes and other biomolecules related to neurotoxicity and Alzheimer's disease (AD). APE1 a multifunctional protein, functions in DNA repair and plays a key role in cell survival versus cell death upon stimulation with cytotoxic agent, making it an attractive emerging therapeutic target. The objective of the present study was to assess potential of curcumin and resveratrol to treat oxidative stress in neuronal death and inflammation in Alzheimer’s disease of AlCl3 induced rat models. Wistar rats were treated with aluminum chloride (25 mg/ kg AlCl3 daily by oral gavage) for 28 d to ensure neurotoxic concentration in hippocampus and hypothalamic region, part highly active in memory control and cognition. Neuroinflammation development was assessed by histological analyses and by investigating associated indices [β-secretase (BACE1), amyloid protein precursor (APP), presenilin (PSEN-1), and PSEN-2)]. Furthermore we measured the expression profile of lethal-7 (let-7) miRNAs members a, b, c, e, and f, a highly abundant regulator of gene expression in the CNS. Protein and mRNA levels of neuroinflammation markers COX-2, BACE1, APP, and iNOS were also attenuated by combined therapy. On the other hand, assessment of the indicated five let-7 members, showed distinct expression profile pattern in the different groups. Let-7 a, b, and c disappeared in the induced group, an effect that was partially suppressed by co-addition of either Cur or Resv. Attention is also paid to mechanisms by which Cur & Resv affect neuronal survival/apoptosis and proliferation/differentiation balance, as well as synaptic plasticity; these data suggest that the combined treatment induced significantly the expression of the five members when compared to rats treated with Cur or Resv only as well as to self-recovery group. The present study clearly indicates the possible benefit from the synergistic effect of Cur-Resv combination as therapeutic agents for neuroinflammation and its associated disorders in counteracting the damage inflicted by Al on rat brain region
Ahmet Mithat Tavli
University of Istanbul-Medipol, Turkey
Title: Neurometabolıc evıdences for dıabetes and ıntermıttent explosıve dısorder: A case report
Time : 15:05--15:25
Biography:
Ahmet Mithat Tavli is currently working at University of Istanbul-Medipol, Turkey
Abstract:
Background: Despite studies suggesting that increased insulin resistance and higher fasting glucose levels may secondary lead to glucose hypo metabolism in specific brain regions which may contribute to the development of cognitive disturbances during diabetes1-2,t he underlying mechanism of diabetes associated impulse control disorders is still unclear. Interestingly, a very recent study has demonstrated that impulse control disorders (especially intermittent explosive disorder) were significantly associated with the diabetes diagnosis. Thus, studies have reported that intermittent explosive disorder and borderl ine personality are associated with an increase of glucose metabolism in the limbic system and a decrease in prefrontal regions supporting the role of dynamically interacting cortico-subcortical networks. Besides their key role as a pacemaker for cortical centers via purely motoric coordination, lentiform nucleus and pons have been also shown to play a significant role in emotional process in also involving reflexive emotional reactions. This is in line with previous evidences showing that gray matter volume reductions in neocortical regions may be specific to psychiatric disorders. These findings together suggest that a disturbance in connectivity between different brain regions, rather than abnormalities within the separate regions themselves, may be responsible for the clinical symptoms of intermittent explosive disorder. Case: Here we describe a 36-year-old man, experience the aggressive outburst symptoms one year after he was diagnosed as type 2 DM. The patient describes severe physical and verbal violence precipitated by little provocation and fulfilled the DSM-IV diagnostic criteria for intermittent explosive disorder. On psychiatric examination, he was cooperative, alert, and fully oriented and displayed an appopriate emotional display. Psychiatric and neurological examinations were otherwise normal. The patient scored eight points of sum score on Modified Overt Aggression Scale. Mini-Mental State Examination and the original Beck’s Depression Inventory revealed no abnormality. Detailed bloodtests were found to be normal except significantly elevated HbA1c levels(13%). A magnetic resonance imaging scan of the brain performed on the admission day showed no abnormality. In contrast, reduced glucose uptake in PET was prominent on the left pontin area, left temporoparietal cortex and lentiform nucleus. Dıscussıon: In our case, functional abnormalities did not entirely parallel morphological changes, and were found in the temporoparietal and subcortical regions which appeared to be rather unaffected in MRI. This indicates that the reduced glucose uptake observed in the respective cortical regions may reflect secondary deficits due to diminished functions of emotional circuits involving the basal ganglia and brain stem and suggest that diabetic individuals may be vulnerable to lower cerebral glucose metabolism in regions implicated in the pathogenesis of intermittent explosive disorder. In conclusion, we present a typical presentation of presumed emotional incontinency in a 36-year-old man with diabetes and the correlation of the metabolic changes seen with his change in emotional state. This type of quantitative analysis can provide that information, unlike a subjective radiological evaluation limited with MRI and CT. A greater understanding of the functional activity of the underlying regions affected by diabetes and intermittent explosive disorder may help to provide insight into specific networks involved.
Stephanie M Schindler
University of British Columbia Okanagan, Canada
Title: Glial receptors for extracellular mitochondrial transcription factor A (TFAM): Potential new therapeutic targets in the treatment of neurodegenerative diseases
Time : 15:25-15:45
Biography:
Stephanie M Schindler completed her BSc at the University of British Columbia Okanagan and is currently completing her MSc at University of British Columbia Okanagan. She has published 5 papers in the field of neuroscience.
Abstract:
Neuroinflammation contributes to the progression of neurodegenerative disorders including Alzheimer’s disease. Evidence indicates that over-activation and dysregulation of microglia, which are the primary immune effector cells of the brain, contribute to neuronal death. Microglial activation in Alzheimer’s disease could be triggered not only by amyloid peptides, but also by other endogenous molecules including damage-associated molecular patterns (DAMPs), which are released upon cellular stress and damage. We hypothesized that mitochondrial transcription factor A (TFAM) could function as a DAMP in the brain since in addition to its intracellular role as a regulator of mitochondrial DNA transcription, extracellular TFAM has been implicated as a DAMP in the peripheral tissues. Our preliminary data indicated that TFAM induced pro-inflammatory and cytotoxic responses of human microglia. In this study, using an in vitro human cell culture system we show that the cellular effects of TFAM are partially mediated by the receptor for advanced glycation endproducts (RAGE) and macrophage-1 antigen (Mac-1). RAGE was implicated by experiments that showed heparin attenuating TFAM-induced human monocytic THP-1 cell toxicity towards SH-SY5Y neuronal cells. Furthermore, heparin decreased the release of monocyte chemoattractant protein (MCP)-1 from activated THP-1 cells. Blockade of the Mac-1 receptor by a specific antibody also attenuated the toxicity of THP-1 monocytic cells towards SH-SY5Y neuronal cells. Identifying the receptors and the intracellular signaling pathways that mediate glial effects of extracellular TFAM could help develop novel therapeutic strategies for neurodegenerative diseases, such as Alzheimer’s, which are characterized by cell damage and associated sterile neuroinflammatory responses.
Lindsay J Spielman
University of British Columbia Okanagan, Canada
Title: Modulation of microglia-mediated neuroinfl ammation as a novel aspect of insulin activity in the central nervous system
Time : 15:45-16:05
Biography:
Lindsay J Spielman completed her BSc with distinction from Vancouver Island University and is currently completing her PhD at the University of British Columbia Okanagan. She has published 4 papers in the fi eld of neuroscience and an additional 4 publications in the field of education.
Abstract:
Recently, type 2 diabetes (T2D) has been identifi ed as a risk factor for Alzheimer’s disease (AD). Peripheral infl ammation and insulin resistance characterize T2D, while AD brains display chronic neuroinfl ammation, and central nervous system (CNS) insulin defi ciency. Th e role of insulin in neuronal survival and plasticity has been described extensively; additionally, this hormone is known to regulate peripheral infl ammation. We hypothesized that infl ammation link T2D with AD. Using an in vitro human cell culture system we investigated the effects of insulin on neuroinflammation. We demonstrate that human primary microglia express insulin receptors and insulin receptor substrates. We further show that insulin upregulates the secretion of interleukin (IL)-8, and suppresses the secretion of monocyte chemoattractant protein (MCP)-1 by stimulated human microglia.Additionally, we show that insulin reduces the toxicity of stimulated human THP-1 monocytic cells (used as a model of microglia) towards human SH-SY5Y neuronal cells. Th ese data demonstrate that insulin can affect the viability of neurons not only directly, but also indirectly by modulating glial cell secretions, which in turn impacts the survival of surrounding neuronal cells. This novel insulin-microglial interaction may provide new targets for drug development and therapies aimed at alleviating the symptoms and progression of AD.
Gabriela Caraveo
Whitehead Institute for Biomedical Research, USA
Title: FKBP12 and calcineurin matter: Repurposing FK506 to ameliorate synucleinopathies
Time : 16:05-16:25
Biography:
Gabriela Caraveo is a Postdoctoral Associate in the laboratory of Susan Lindquist at the Whitehead Institute for Biomedical Research. She completed her undergraduate studies at the department of Biology, School of Sciences at the National Autonomous University of Mexico (UNAM) in Mexico City. She then went to Johns Hopkins University as a Fulbright Scholar in 1999, where she obtained her PhD in Immunology in 2007. Her research seeks to understand the role of calcium signaling pathways in neurodegenerative diseases such as Parkinson Disease using diverse model systems, from yeast to mammalian neuronal models.
Abstract:
Calcineurin is a highly conserved Ca2+ calmodulin-dependent phosphatase that plays a key role in sensing Ca2+ concentrations and transducing that information into cellular responses. α-Synuclein (α-syn) is a small lipid binding protein whose misfolding and accumulation in Lewy Bodies is a pathological hallmark of several neurodegenerative diseases collectively known as synucleinopathies for which Parkinson’s Disease (PD) is the most prevalent. We previously showed that α-syn overexpression leads to high rises in cytosolic Ca2+ leading to an over-activation of calcineurin which dephosphorylates a subset of substrates that result in toxicity. Decreasing, but not eliminating calcineurin activity with compounds such as FK506 shift s the spectrum of substrates and results in protection. FK506 impairs calcineurin function by locking it into a complex with the immunophilin FKBP12. Through an integrated genetic and unbiased whole shotgun proteomic approach we now establish the importance of FKBP12 in modulating α-syn toxicity in both calcineurin-dependent an independent manner. Moreover, we demonstrate the efficacy of FK506 in vivo using a rat model for PD. FK506 has the ability to cross the blood brain barrier and is an FDA approved drug typically used as an immunosupressant in the clinic. Since our findings establish the importance of modulating FKBP12 activities at sub-immunosupressive doses to achieve neuroprotection, FK506 could immediately translate into the clinic to treat patients with synucelinopathies such as PD.