Day 2 :
Keynote: A novel approach to prevent Alzheimer’s, Parkinson’s and ALS diseases phenotypes in situ and in transgenic mice models using a small peptide derived from cyclin - dependent kinase 5 (Cdk5) neuron specific activator protein, p35
Time : 09:30-10:00
Pant received his M.A. and Ph.D. degrees in Physics from Agra University, Agra, India. His postdoctoral studies were conducted on the mechanisms of electron and ion transport in model membrane systems at the Department of Biophysics at Michigan State University. He joined the Laboratory of Neurobiology in the NIMH as a senior staff fellow in 1974 with Dr. Ichiji Tasaki where he studied the function of the axonal cytoskeleton in the squid giant axon. In 1979 he moved to the NIAAA extending his studies on the neuronal cytoskeleton and the effects of alcohol on its regulation. Dr. Pant moved to the NINDS, Laboratory of Neurochemistry in 1987 where he is presently chief of the section on Cytoskeleton Regulation. His laboratory is studying the mechanisms of topographic regulation of neuronal cytoskeleton proteins by post-translational modification, including the role of kinase cascades in normal brain and during neurodegeneration.
Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs), it has been now well documented thatrncyclin-dependent kinase 5 (Cdk5), a critical neuronal kinase in nervous system development, function and survival whenrnderegulated and hyperactivated induces AD and ALS like phenotypes in mice. Under physiological conditions, Cdk5 activity isrntightly regulated. The deregulation and hyperactivation of Cdk5/p25 due to neuronal insults and toxicity induces neuropathology.rnThus Cdk5/p25 becomes prime therapeutic target for AD and other neurodegenerative diseases associated with the hyperactivationrnof Cdk5. In order to prevent hyperactivation of Cdk5/p25, we have designed several small peptides of p25 on the basis of Cdk5/rnp25 crystal structure and molecular modeling, evaluated for competition with p25 and thus inhibiting selectively the hyperactivityrnof Cdk5. We discovered a small peptide (p5) comprising of 24 amino acids inhibited Cdk5 hyperactivation. The modified of p5rnto TFP5 crosses blood brain barrier (BBB) and was examined its therapeutic role in transgenic AD and ALS model mice. The p25rntransgenic AD model (p25Tg) and 5XFAD mice were chosen since these mice show similar phenotypes to AD patients. Post TFP5rninjections in p25Tg mice, 5XFAD and ALS model mice displayed significant reduction in Cdk5/p25 hyperactivity, Aβ plaquernformation along with behavioral rescue. TFP5 does not inhibit normal Cdk5/p35 activity and therefore has no toxic side effects.rnIn addition, treated mice rescued synaptic dysfunction, neuroinflammation and a reduction in phospho-neurofilaments/tau andrnneuronal cell death. These results indicate that TFP5 has a potential role as a therapeutic candidate for AD, ALS and other relatedrnneurological diseases.
University of Nottingham, UK
Time : 10:00-10:30
Wayne Grant Carter received his Honours degree and PhD in Biochemistry from the University of Southampton, studying protein post-translational modification and\\\\r\\\\nmolecular signalling cascades. He is currently a Group Leader in the School of Medicine, University of Nottingham, with research focused upon protein post-translational\\\\r\\\\nmodification and molecular mechanisms of hepato- and neuro-toxicity. His recent publication detailing “alcohol-related brain damage in humans” (PLoS ONE 9(4): e93586)\\\\r\\\\nreceived considerable national and international media coverage
The mechanism by which neurotoxicants, such as alcohol, damage neurons is not fully understood. To investigate the\\\\r\\\\nneuropathology arising from cumulative excessive alcohol consumption we examined prefrontal cortex brain tissue from human\\\\r\\\\nalcoholics and age, gender, and post-mortem delay matched control subjects. H&E staining and light microscopy of prefrontal\\\\r\\\\ncortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a\\\\r\\\\ndisruption of subcortical neuron patterning in alcoholic subjects. One dimensional polyacrylamide gel electrophoresis proteomics\\\\r\\\\nof cytosolic proteins identified dramatic reductions in the protein levels of spectrin β II, and α- and β-tubulins in alcoholics, and\\\\r\\\\nthese were validated and quantitated by Western blotting. In alcoholics, significant loss of cytosolic α- and β-tubulins was also\\\\r\\\\nseen in the other brain regions examined: caudate nucleus, hippocampus, and cerebellum. We have also extended our studies to\\\\r\\\\nassess brain damage in rats administered alcohol for a 4-week period. Results of this short-term (acute) alcohol exposure will also\\\\r\\\\nbe discussed.
Medical University of South Carolina ,USA
Keynote: To be Updated Soon
Time : 10:30-11:00
Mark S. Kindy, Ph.D. is Professor of Neurosciences at the Medical University of South Carolina, Adjunct Professor of Bioengineering at Clemson University, Adjunct Professor of Chemical Engineering at the University of South Carolina, Adjunct Professor of Management and Entreprenurialism, School of Business, College of Charleston. He received his BA in zoology from the University of Massachusetts in 1980. Dr. Kindy received his Ph.D. in Biochemistry from Boston University School of Medicine from 1982-1987. He was a post-doctoral fellow at the Salk Institute from 1987-1989 in Molecular Biology and Virology. From 1989-2002, Dr. Kindy was a faculty member in the Department of Biochemistry at the University of Kentucky and rose from Assistant Professor to Full Professor. Dr. Kindy is currently the Admiral Pihl Endowed Professor in the Department of Neurosciences. Dr. Kindy is also a Research Career Scientist at the Ralph H. Johnson VA Medical Center in Charleston. Dr. Kindy has served on many NIH, AHA, AA review panels, has reviewed for many journals and is currently on the editorial board of 10 journals. Dr. Kindy has over 140 peer reviewed publications and is funded by the NIH, VA , NSF and several foundations.
University of Colorado, USA & Gothenburg University, Sweden
Title: Complementary and alternative medicine-based interventions for traumatic brain injury: Translating research (basic and clinical) into evidence-based practice
Time : 11:20-12:50
Theresa D Hernandez, Ph.D. has been studying traumatic brain injury (TBI) using basic and clinical neuroscience models since 1985. Her ongoing, extramurally funded research program assesses the degree to which recovery and functional outcome after TBI can be optimized in a variety of populations (Veterans, civilians, athletes). This includes conducting randomized, placebo-controlled, blinded trials of novel interventions, such as acupressure. This work is accomplished through her appointment as Professor and Chair of the Department of Psychology & Neuroscience at CU Boulder, her appointment as a Senior Investigator and Research Psychologist in the Eastern Colorado Healthcare System, Rocky Mountain MIRECC (Mental Illness, Research, Education & Clinical Center) and through her role as one of the co-Directors of the PAPRR (Promoting Athlete Performance, Recovery and Resilience) Board at CU Boulder. She is also the Director of the CAIRR (Clinical Assessment of Injury, Recovery and Resilience) Neuroscience Laboratory.
Objective: Presentation of current challenges and opportunities associated with CAM (complementary and alternative medicine) research and clinical applications in Civilian, Veteran and Military Service populations in the U.S. and Europe. Following a brief overview of CAM, there will be a discussion of translational capacity from basic to clinical research to clinical practice, as well as how to develop an adoptable evidence base, with proof of effectiveness. Methodological and ethical challenges associated with CAM research in those with traumatic brain injury and co-morbidities will also be described in terms of how these challenges relate to practice and policy issues, as well as implementation and dissemination. CAM modalities to be covered will include acupressure and mindfulness–based stress reduction with an emphasis on lessons learned from the laboratory and the clinic.
- Novel Treatment strategies 1
Location: Guggenheim Room
Natalie L Rasgon
Stanford University School of Medicine, USA
T Chris Gamblin
University of Kansas, USA
Mark Kindy is Professor/Associate Chair for Research in the Department of Regenerative Medicine and Cell Biology at MUSC and Senior Research Career Scientist/Deputy ACOS for Research at the VA Medical Center in Charleston, SC. He received his BS from the University of Massachusetts in Zoology and PhD from Boston University School of Medicine in Biochemistry. He was a postdoctoral fellow at the Salk Institute. He was at University of Kentucky in the Department of Biochemistry and the Center on Aging. His area of expertise is neurodegenerative disorders, animal modeling, mechanisms associated with diseases and regeneration of the brain.
There are currently no effective therapeutic agents for traumatic brain injury (TBI), but drug treatments for TBI can be developed by validation of new drug targets and demonstration that compounds directed to such targets are efficacious in TBI animal models using a clinically relevant route of drug administration. The cysteine protease, cathepsin B, has been implicated in mediating TBI, but it has not been validated by gene knockout (KO) studies. Therefore, this investigation evaluated mice with deletion of the cathepsin B gene receiving controlled cortical impact TBI trauma. Results indicated that KO of the cathepsin B gene resulted in amelioration of TBI, shown by significant improvement in motor dysfunction, reduced brain lesion volume, greater neuronal density in brain, and lack of increased proapoptotic Bax levels. Notably, oral administration of the small-molecule cysteine protease inhibitor, E64d, immediately after TBI resulted in recovery of TBI-mediated motor dysfunction and reduced the increase in cathepsin B activity induced by TBI. E64d outcomes were as effective as cathepsin B gene deletion for improving TBI. E64d treatment was effective even when administered 8 h after injury, indicating a clinically plausible time period for acute therapeutic intervention. These data demonstrate that a cysteine protease inhibitor can be orally efficacious in a TBI animal model when administered at a clinically relevant time point post-trauma, and that E64d-mediated improvement of TBI is primarily the result of inhibition of cathepsin B activity. These results validate cathepsin B as a new TBI therapeutic target.
University Lancaster, UK
Title: Retro-inverso peptide inhibitors of β-amyloid oligomer formation as a novel treatment for the progression of Alzheimer’s disease
Time : 13:50-14:10
David Allsop is Professor of Neuroscience at Lancaster University. He has been working on Alzheimer’s disease for around 30 years, and has published more than 120 papers on this and other neurodegenerative diseases. He is a member of the Research Executive Committee of The Alzheimer’s Society, UK.
Inhibition of Aβ oligomer formation could have a major impact on clinical progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). We are working on retro-inverso (RI) peptides and RI-peptides attached to the surface of nanoparticles as therapeutically useful inhibitors of early-stage Aβ aggregation. The inhibitor RI-OR2-TAT consists of the Aβ binding peptide RI OR2 (rGffvlkGr) attached to a retro-inverso version of the transit peptide ‘TAT’ to target the inhibitor into the brain. Fluorescein-RI OR2-TAT has been shown to cross the blood brain barrier (BBB) of APPswe/PS1ΔE9 transgenic mice and bind to β amyloid plaques. Moreover, daily peripheral injection of RI-OR2-TAT into these mice for 21 days resulted in a 25% reduction (p<0.01) of Aβ oligomer levels, a 32% reduction (p<0.0001) of amyloid plaque count, a 44% reduction (p<0.0001) in the numbers of activated microglial cells, and a 25% reduction (p<0.0001) in oxidative damage. Covalent attachment of RI OR2 TAT to liposomes, to produce peptide-inhibitor nanoparticles (PINPS), has resulted in a remarkably potent multivalent inhibitor that has several advantages over the free peptide for further development as a potential drug. These include biocompatibility, stealth properties (to avoid detection by the immune system) and the possibility of designing multi-ligand systems directed at more than one target. Various drug candidates aimed at inhibiting the formation of Aβ, or inducing the clearance of senile plaques from the brain, have failed in recent years. Our RI peptide and nanoparticle-based therapies are an alternative approach to more conventional drugs and could offer some hope for success in future human clinical trials.
University of Kansas, USA
Time : 14:10-14:30
Chris Gamblin completed his PhD with Dr. Robley Williams, Jr. at Vanderbilt University and postdoctoral studies with Dr. Skip Binder at Northwestern University Feinberg School of Medicine. He is currently an Associate Professor in the Department of Molecular Biosciences at the University of Kansas and continues to investigate the biochemical mechanisms of tau aggregation.
The abnormal aggregation of the microtubule-associated protein tau is believed to result in cell death and cognitive deficits in Alzheimer’s disease and several other neurodegenerative diseases. The inhibition and reversal of tau aggregation would likely have therapeutic benefit for the treatment of such disorders. In our efforts to identify tau aggregation inhibitors (TAIs), we have sought to mine the secondary metabolome of the fungus Aspergillus nidulans for unique compounds with anti-aggregation properties. Fungal natural products have historically been a rich source of biologically important compounds ranging from anti-cholesterol medications to antibiotics. By screening just a small library of A. nidulans natural products, we were able to identify three lead compounds capable of inhibiting tau aggregation. One of these, asperbenzaldehyde, represented a novel class of TAI. Because asperbenzaldehyde is a precursor to the chemical class of azaphilones, we subsequently generated and analyzed the TAI activity of 11 azaphilone derivatives in vitro. We found that all azaphilone derivatives tested inhibited tau aggregation. Four of the compounds also caused the disassembly of pre-formed filaments in a dose-dependent fashion by reducing both the length and number of tau filaments. Tau also retained significant microtubule-stabilization activity even in the presence of the most potent TAI, indicating that the azaphilone scaffold may be a very promising structural core for future development of tau therapeutics.
Institute of Psychopathology, Italy
Title: Variation in response to short-term antidepressant treatment between patients with continuous and non-continuous cycling Bipolar disorders
Time : 14:30-14:50
Rocco de Filippis completed his MD and PhD from Catholic University of the Sacred Heart in Rome. Investigator Meeting (Western Europe and North America) for BRENDA/pharmacological Study on Nalmefene (LUNDBECK - pharmaceutical company). Barcellona (Spagna) . He holds a Master’s degree and he improved respectively in Bipolar Disorders and Addictive behavior in the years 2011/2012. He currently works and at the Institute of Psychopathology - Rome as a Psychiatrist and Addictive Medicine, and up to now presented as scientific coordinator of CME and Master of Addictive Behaviors; he currently publishes on Bipolar Disorders with high specialization on rapid cycling;he is also an official candidate at the Psychoanalytic Italian Society of the First Italian Center of Rome, and member of IPSO (International Psychoanalytic Studies Organization). He had a oral speech at Translational Medicine 2014 in Las Vegas on QTc Prolungation and Psychotropic Drugs.
Objectives The study aimed to compare effectiveness and safety of short-term antidepressant treatment between patients with continuous (CCC) and non-continuous (N-CCC) cycling bipolar disorders. Methods The study sample included 101 patients with bipolar disorder, 22 (21.8%) CCC and 79 (78.2%) N-CCC. Response was defined as a HDRS21 total score <7 at 12 weeks of treatment and remission as a ≥50% reduction of baseline HDRS21 total score sustained for 8 weeks. Results Compared with N-CCC patients, CCC patients achieved a significantly lower percentage of response (respectively 50% vs. 82.3%, χ2=9.6, p=0.002) and remission (respectively 40.9% vs. 69.6%, χ2=6.11, p=0.013). Adjusted logistic regression analysis indicated that CCC patients were 4.3 times more likely to be non-responders and 3.3 times more likely to be non-remitters than N-CCC patients. Concerning AD safety, 1 (5.0%) CCC patient committed a suicide attempt and AD-emerging switch was observed in 2 patients with N-CCC (2.5%) and in 1 with CCC (4.5%). Limitations The observational nature of the study, retrospective assessment of course, and unblinded outcomes assessment. Conclusions Our findings indicate that the presence or absence of a free interval identifies two different forms of bipolar disorders with different response not only to prophylactic treatment, as previous reported, but also to short-term ADs. We submit that clinicians should take into consideration their patients\' pattern of cycling when prescribing short- term AD treatment. Moreover, subtypes of bipolar disorders might be used as moderators of treatment response in studies assessing the efficacy or the effectiveness of antidepressant treatment.
St George’s University, London
Time : 14:50-15:10
I obtained a degree in Chemistry from Oxford, and a PhD in Biochemistry from London University. I acquired skills in protein science at UCLA in the 60’s, and an interest in brain peptides by working on endorphins at NIMR in the ‘70s. I started investigating the role of peptides and cellular protein mis-targeting in AD at St George’s in 1995, and found that raised cholesterol was a risk factor for -amyloid formation, and the small peptides were possible therapeutics.
-Amyloid peptides were isolated from plaques in post-mortem brains of Alzheimer’s patients some 40 years ago. Three types of evidence suggest they are causative in the cognitive loss of Alzheimer’s Disease (AD). (1) Mutations in the amyloid precursor gene (APP) and -secretase gene (PS1) responsible for its formation, are found in early-onset AD patients. These mutant gene expressed in transgenic mice give rise to memory defects. (2) The total amount of -amyloid in post-mortem brain correlates with the extent of cognition loss prior to death. (3) Aggregates of -amyloid proteins are toxic to neuronal cells in vitro and in vivo. In the last seven years, it has become clear that soluble oligomers of -amyloid block the synaptic plasticity required for memory formation and storage, whereas fibrils of insoluble -amyloid are relatively innocuous. Potential therapy against -amyloid has developed along two lines. First, vaccines against the peptide have been shown to clear amyloid plaques in patients, but have little effect on cognitive status. The suggestion is therefore, that therapy should be aimed at the formation of new oligomers of -amyloid, rather than clearance of mature fibril -amyloid in plaques. We have developed a number of retroinverted peptides that prevent formation of soluble amyloid oligomers, shown to prevent neurotoxicity to cells in culture. Some of these peptides have been converted into gadolinium-containing MRI contrast agents, and shown to be useful for -amyloid detection in the brains of 5xFAD transgenic mice.
National Cheng Kung University, Taiwan
Title: Anti-Inflammation and neuroprotective drugs benefit the treatment of Bipolar II disorder patients
Time : 15:10-15:30
Distinguished Professor Ru-Band Lu graduated from National Defense Medical center Taipei, Taiwan, in 1972. He became a professor of Psychiatry at National Defense Medical Center in 1989. 1992 to 1993, he was a visiting scientist in Human Genetics at Yale University, New Haven, CT; he studied genetics, psycho-neuroimmune pharmacology. 2003 to 2009, he was the director of the Institute of Behavioral Medicine, National Cheng Kung University, Tainan, Taiwan. In this decade, he works in the developmental navel treatment model. He has published more than two hundred research articles in the recent fifteen years.
Low dose memantine might possess anti-inflammatory and neuroprotective effects mechanistically remote from the NMDA receptor. We investigated whether using valproic acid (VPA) add-on memantine (5 mg/day) to treat bipolar II disorder (BP-II) is more effective than using VPA alone. In this randomized, double-blind, controlled 12 week study, BP-II patients were randomly assigned to a group: VPA+Memantine or VPA+Placebo (Pbo). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical response, alone with plasma levels of tumor necrosis factor (TNF-α), interleukin 6 (IL-6), IL-8, and IL-1and metabolic profiles during week 0, 1, 2, 4, 8 and 12. After 12 weeks, there was a significant increase of high-density lipoprotein cholesterol (HDL-C) (p < 0.009) in the memantine group compared with the Pbo group. The TNF-α were significantly decreased in the memantine group than in the Pbo group (P = 0.013). The changes in HDRS score were significantly associated with changes in IL-6 (P = 0.012) and IL-1(P = 0.005) levels; changes in YMRS score associated with changes with TNF-α(P = 0.005) level changes. The association between BDNF Val66Met polymorphism with treatment response was evaluated. After stratified byBDNF Val66Met genotypes, significantly greater decreases in HDRS scores were found in the VPA+memantine group in patients with the Val/Met genotype (p=0.004). We conclude that memantine might benefit treatment of BP-II via decreasing cytokines and increasing HDL-C. The BDNF Val66Met polymorphism influences responses to add-on memantine by decreasing depressive symptoms in BP-II.
University of Mississippi , USA
Time : 15:30-15:50
Christopher J. Lahr is an associate professor in the departments of surgery, medicine and obstetrics and gynecology at the University of Mississippi Medical Center.
The vagus nerve ganglion inside the skull has an auricular branch (Arnold's nerve) that passes through Arnold's canal to enervate the sensory receptors in the inner surface of the inside of the concha of the external ear. If you stimulate Arnold's nerve you cause vagal stimulation. Arnold nerve stimulation via an earbud delivering electrical stimuli has been used in Europe to treat depression. It is possible that this electrical stimulation could be achieved with a simple smartphone app and acoustic earbuds. We have reviewed our experience with 54 patients diagnosed with gastroparesis into which we have placed gastrointestinal electrical stimulators then studied their results based upon Likert scale quantification of symptoms, neuronal cell counts of full thickness gastrointestinal biopsies, electrogastrographic evidence of GI electrical wave frequency and amplitude to personalize electrical stimulation by adjusting voltage (amplitude), frequency, pulse with and cycle times. 59% of patients showed immediate changes in electrical rhythm as well as symptomatic relief. Direct gastric electrical stimulation appears to have an effect on vagal mediated symptoms. This very preliminary data raises the possibility that direct vagal electrical stimulation (instead of indirect vagal stimulation via the gut) of the gut may have an impact upon other vagus mediated reflexes as well, such as its beneficial effect upon depression and epilepsy. Our current technique would use off the shelf devices to transcutaneously stimulate the vagus nerve or one of its branches to determine if such stimulation has an impact upon depression and epilepsy. The transcutaneous stimulation of the vagus nerve via its auricular branch would be achieved with a smartphone app with an internal safety valve. The heart rate is be regularly monitored and vagal stimulation stopped if the heart rate dropped below 60.
- Novel Treatment strategies 2
Location: Guggenheim Room
Harish C Pant
National Institute of Neurological Disorders and Stroke, USA
Mark S Kindy
Medical University of South Carolina, USA
American Institute of Stress , USA
Title: A Novel Hypothesis as to the Origin of Autism: An Alteration in Biological Water Dynamics Disrupts Proton-Coupled Electron Transfer and the Organizing Function of CNS Fractones
Time : 16:10-16:30
Robert Michael Davidson completed his PhD in Pharmaceutical Chemistry at the age of 26 from UCSF, NSF postdoctoral fellowship at the National Bureau of Standards, Center for Analytical Chemistry, MD degree at St Louis University School of Medicine, Nuclear Medicine residency at Baylor College of Medicine, Houston, Texas, and Internal Medicine residency in Phoenix, Arizona. He was Associate Medical Director for DuPont Pharma’s Radiopharmaceutical Division1990-1992. He has published more than 30 papers in peer-reviewed journals. He is a Fellow of The American Institute of Stress (2012-present) and practiced complementary, alternative, integrative internal medicine in Gladewater, Texas (2008 – 2015), for PhyNet Inc.
A new hypothesis as to the organizational basis of cells, organism, and nervous system - the “fractal dimension” - is presented. Alteration in biological water dynamics likely precedes the onset of inflammation, maternal immune activation, and IL-6 elevations, in autism. Exogenous interfacial water stress (EIWS) leads to concomitant disruption of multiple biosemiotic levels, including the heretofore, seldom considered sub-atomic level, i.e. that of the hydrated electron. Biological water at the interphase of proteins in the CNS is self-ordering, fractal, and birefringent. DTI-MRI studies of the brain show loss of fractional anisotropy prior to overt manifestations of brain disorders, including autism. Recent description of “fractones” in the basement membranes of hippocampal subventricular zones of the brainstem is perhaps not by serendipity, the same general location in which several neurotropic viruses and neurotoxicant metal aquo cations, i.e. Al3+, are sequestered. Fractones have been proposed as the organizing features of the HSPGs in the ECM of the CNS and throughout the human body, including the heart, gut, and bone marrow. We propose that the origin of the “fractal dimension” is not that of polyLM, but instead has a subatomic basis, originating from the hydrated electron. While the definitive structure of hydrated electrons is still being explored scientifically, present data has shown it to consist of cyclic hexamers of water, surounding or dispersing the negatively-charged electron density. We proposed a cyclic mesomeric hexameric bipolaron in 2013, as a putative molecular basis for proton-coupled electron transfer. The hydrated electron gives rise to the fractal dimension.
University Hospital Ulm, Germany
Title: Characterization of Microparticles derived from cultured macrophages and cerebrospinal fluid of patients with schizophrenic and affective disorders
Time : 16:30-16:50
Marion Schneider has completed his PhD with honors at the age of 26 years from the University of Bonn, Germany and postdoctoral studies from Institute Pasteur, Paris, France. She finalized her habilitation in 1988 on Immunology and teaches in Immunology in a variety of inflammatory diseases including SIRS, sepsis and neuroinflammation. She leads the Section on Experimental Anesthesiology in Ulm, Germany since 1997. She published more than 250 original manuscripts and provides ample experience on biomarkers in various diseases and signaling. Her current focus are in vivo activated antigen presenting cells.
Inflammatory antigen presenting cells (APC, dendritic cells and macrophages) are characteristic for patients with affective disorders and can be enriched from Ficoll-isolated mononuclear cells by 3-4 weeks of in-vitro culture. Flow cytometry, electron microscopy, Western Blots and cytokine quantification were applied to characterize the cell type and the inflammatory response in blood and cerebrospinal fluid (CSF). These analyses demonstrate that the enriched APC can be classified into either dendritic cells (iDCs), M1 or M2 macrophages. All cell isolates display high macropinocytotic activity and in addition form prominent autophagous vacuoles. The M1 type occurred more often in affective disorders than in schizophrenics. M1 cells expressed the ATP-sensitive P2R7 ion channel. ATP stimulation of the P2X7 ion channel caused the release of plasma membrane vesicles and microparticles (MP). MPs enriched from blood-derived APC cultures and from native CSF were subjected to protein chemical as well as miRNA analysis. All MP preparations were β-actin positive and in part stained for the autophagy marker LC3-II. When compared to the cultured APC-target cells, the microparticles were stronger positive for arginase 1, CD95, S100 and CD178, whereas CD36, and the TNF-R type I (CD120a) were decreased. MiRNA analysis revealed inflammatory signatures in the majority of affective disorders. These results indicate that microparticles may transport protein and miRNA species to target tissues. The current protocol proved to be valid to simultaneously study MP generation in vitro using cultured APC and to isolate and characterize MP from the CSF.
Fraunhofer Institute for Cell Therapy and Immunology, Germany
Title: Targeting Neurotoxic N-Terminal Pyroglutamated Abeta (Pgluaβ) with inhibitors of Glutaminyl Cyclase (Qc) and Pgluaβ-specific antibodies has reached clinical stage
Time : 16:50-17:10
Hans-Ulrich Demuth has completed his PhD at the age of 28 and his doctorate of sciences at the age of 36 years from Martin-Luther-University, Halle/S., Germany. He did postdoctoral studies at University of Kansas and the Uppsala Biomedical Research Center. He has inaugurated and co-founded Probiodrug in 1997, the company which has developed the concept of inhibition of Dipeptidylpeptidase-4 as treatment of type-2 diabetes (on the market since 2006). He has published more than 300 papers in reputed journals and has been serving as an editorial board member and reviewer of repute. In 2013 he founded the Fraunhofer-IZI department MWT.
Alzheimer’s disease (AD) is characterized by neuron-loss and neuro-inflammation. Although N-truncated and N-pyroglutamated Aβ-peptides (pGluAβ) are known as prominent constituents of plaques in AD-brain, their importance was overseen and pathways leading to their formation not understood. Because of their abundance, resistance to proteolysis, such N-terminally modified peptides can be important for initiation of pathological cascades leading to AD. Our work uncovers, that N-terminal pGluAβ-formation is catalyzed by QC1. QC-expression is upregulated in the cortex of individuals with AD and correlated with the appearance of pGlu-modified Aβ. Oral application of QC-inhibitors resulted in reduced pGlu3Aβ42 burden, but surprisingly also to the attenuation of the 1.000fold higher amounts of total Aβ in transgenic AD-models1. These observations led to the hypothesis that pGluAβ can seed Aβ-oligomerization by self- and co-aggregation with other monomeric Aβ-species2. Amounts of less than 10nM pGlu3Aβ42 generated cytotoxic oligomers which are over 20 fold more stable than oligomers of “classical” full-length Aβ-peptides. Such mixed pGlu3Aβ42-oligomers propagate their toxic structure in a prion-like manner. Moreover, the neurotoxicity unfolds to be tau-dependent in cell culture as well as in animal models. There, specific neuronal expression of pGluAβ provides in vivo evidence for profound pGluAβ neurotoxicity and gliosis induction2. Hence, a drug development program was entering regulatory testing 2010. Two phase 1: Single (SAD) and multiple ascending dose (MAD) trials of the compound PQ912 in healthy volunteers were conducted. They revealed PQ912 safe and well tolerated. Dose-proportional pharmacokinetics and a strong pharmacodynamic relationship were observed in plasma and CSF justifying studies involving patients. PQ912 is the first QC-inhibitor for treatment of AD since March 2015 in phase 2. Our research concentrates further on posttranslational modifications of Aβ leading to alternative pathways of the turnover of precursor protein APP.
University of Haifa, Israel
Title: Error Augmentation as a Possible Technique for Improving Upper Extremity Motor Performance after a Stroke- a pilot study
Time : 17:10-17:30
Carmeli is an Associate Professor in the Physical Therapy Department at Haifa University. He is the chairperson of the Master Degree program in the university. He served for six years as the Chief Editor of the \"Israeli Physiotherapy Journal\". His main research and teachings areas are Physical Function at advanced age, and biology of skeletal muscle.
Enhancement of motor performance is crucial in rehabilitation after a stroke. A new concept in motor learning and rehabilitation is error augmentation: using erroneous sensory feedback to enhance adaptation to a new environment. However, the clinical efficacy of this method to enhance motor learning after a stroke needs to be evaluated. To determine the efficiency of Error-Augmentation therapy over sham robotic training for the enhancement of the upper extremity motor performance after a stroke. Ten patients after a stroke randomly assigned into study or control groups. The study group (EA) executed error-augmentation training using DeXtreme robotic interface with the activation of a force field, while the control group (Cont.) executed a robotic training using the same devise, without the activation of the force field. Both groups carried out 12 treatment sessions by the same protocol. The effect of treatment was measured by the robotic devise by two objective outcomes: 1) Mean trajectory error; 2) Total performance score in hand reaching. The study group (2802 ± 473) and the control group (1160 ±1155) displayed an increase in total performance score, and reduction in mean error (6.2 ± 5.5 and 2.2 ± 4.5 respectively), in four weeks of error-augmentation treatment for the upper extremity. Error augmentation training implemented by robotic interface has been shown to potentially be an efficient platform to enhance upper extremity motor performance after a stroke.
Taras Shevchenko National University of Kyiv, Ukraine
Time : 17:30-17:50
Makarenko O.M. has taken PhD degree at the age of 30 at the Moscow medical stomatological institute, M.D. degree at the age of 40 at the Institute of higher nervous activity in Moscow. He carries out his post-dock researches at the Institute of higher nervous activity and T. G. Shevchenko national university of Kiev. He is a professor of the psychology department, the author of more than 100 articles in reputed journals and 4 monographs (Lambert Academic Publishing).
Trophinotropins (TT) or neurotrophinotropic growth factors (NGF) are the group of endogenous therapeutic factors, which are actively secreted by cells of the organism being in the state of restoration after pathological process modeling or under recovery/remission. A distinctive feature of TT action is the activating influence on the cells of damaged tissues and organs along with their protective and immune-corrective mechanisms of action. «Cerebral» is the agent separated from nerve cells of the cerebral cortex of pigs, experienced bihemispheric autohemorrhagic stroke. It contains a complex of low-molecular pharmacologically active peptides (less than 1200 Da). The drug is characterized by its cerebrotropic multimodal action on nerve cells, which main effect is a trigger trophinotropic regulatory action on secretion of NGF and other cytokines. «Cerebral»’s application increases the level of synthesis and secretion of NGF in the conditions of experimental hemorrhagic stroke and at the same time does not influence synthesis and secretion of this growth factor in the intact animals. In the experiment, NGF secretion in the CNS was increased under intranasal way of introduction because the concentration of mRNA NGF was 0,05-0,74 pmol/l on the 2nd day after introduction (whereas concentration under intraperitoneal introduction was 0,05-0,10 pmol/l mRNA on the 2nd day) at the expense of express delivery of its molecules into the brain. The drug showed neuro-activating action in acute and remote from the beginning of stroke deseases periods, modifies cellular metabolism, restores unconditional reflex reactions and lost functions, activates the process of intellectual and psychoemotional activity.