Caffeine: A Life Saver Drug?

Sandip Paul^* and Bhanita Sharma

Indian Institute of Technology Guwahati, India

We perform classical molecular dynamics stimulation techniques to investigate the role of caffeine in inhibiting amyloid aggregation. We have first tried to understand the self-association of caffeine molecules in aqueous solution. Then we extend our study towards molecular interaction between caffeine and protein oligomers, which shed lights on the mechanism of amyloid inhibition by caffeine. She proposed that caffeine has the ability to inhibit amyloid formation of peptide, and the blocking of aromatic Phe-residue of the Aβ₁₆₋₂₂ peptide by caffeine clusters through peptide-caffeine π-stacking interaction, and other residues by hydrophobic and hydrogen bonding interactions lead to complete disaggregation of peptide in caffeine solution with 10:1 or higher caffeine to peptide stoichiometric ratio.

Biography:
Sandip Paul is currently Professor of Chemistry at the Indian Institute of Technology (IIT) Guwahati, India. He earned his bachelor of science at University of Burdwan, West Bengal, India and his PhD in Theoretical/ Computational Chemistry from Indian Institute of Technology (IIT) Kanpur, Uttar Pradesh, India. After completing his PhD, Sandip joined as a postdoctoral researcher in University of British Columbia, Vancouver, Canada where he spent a couple of years. Thereafter, he moved to University of North Carolina (UNC), Chapel Hill, USA and spent a year as a postdoctoral researcher before finally accepted a faculty position in his present institution IIT Guwahati.

Clinical Correlates with Functional Neuroimaging: From Case Reports to Clinical Researches

Kenichi Meguro

Tohoku University Cyric, Japan

An approach based on behavioural neurology is important for better understanding of 1) behavioural abnormality, 2) neuronal network, and 3) rehabilitation for patients with cognitive impairment. Mainly, neurological background of human behaviour is consisted of three parts, i.e., the hierarchical axis (“old brain” vs “new brain”), the left-right axis (“language brain” vs “nonlanguage brain”), and the anterior-posterior axis (“behavioural brain” vs “cognitive brain”).

1) Behavioural Abnormality

A case with right basal ganglia infarction is reported, who disclosed hyperactivity and confabulation. We found right basal ganglia infarction (MRI) and decreased blood flow to the right frontal lobe (SPECT). After the physician in charge provided an explanation, the patient began to be conscious about her disease and agreed to undergo drug treatment.

2) Neuronal Network

A case with left thalamic infarction is reported, who developed difficulty finding words and used many pronouns in her communication. MRI showed infarction in the left thalamus and SPECT revealed decreased CBF in the bilateral anterior cingulate blood flow. The fronto-subcortical network and the Yakovlev and Papez networks are considered to understand the symptoms.

3) Rehabilitation

A case with vascular MCI is reported, who took a longer time to learn the exercises with decreased working memory capacity. Working memory maintenance promotes long-term memory information. The anterior cingulate cortex plays an important role in dual-task situations. Dual-task during unfamiliar movement could be stressed the working memory capacity. The cingulo-frontal network may be partially blocked by the deep white matter lesions in this case.

Biography:
Kenichi Meguro is a Professor in Geriatric Behavioral Neurology, Tohoku University, Japan. He is a director of Tajiri Skip Center. He Graduated from Tohoku University Graduate School of Medicine. He is a Executive Committee of INA and ASAD, Councilor of Japanese Society of Cognitive Neuroscience, Higher Brain Dysfunction, Neuropsychology Association, Psychogeriatric Association, and Society for Dementia Research.

Role of Microbiota Derived Short Chain Fatty Acids in α-Synuclein Aggregation and Seeding

Giulio Pasinetti^1*, Risham Singh² and Lap Ho²

¹Mount Sinai School of Medicine, USA
²Icahn School of Medicine at Mount Sinai, USA

Objective: To determine whether microbiome derived short chain fatty acid (SCFA) may modulate abnormal α-synuclein misfolding and seeding activity of α-synuclein to support the hypothesis of potential novel therapeutic approaches.

Background: There is growing evidence from both in vivo and in vitro studies that in many neurodegenerative disorders, including synucleinopathies, cell-to-cell transmission of a pathological, misfolded protein occurs and may be a vehicle for spreading of pathology throughout the brain. We hereby investigate whether microbiota-derived SCFAs may help attenuate the misfolding of α-synuclein and their effects on seeding synucleinopathy.

Design/Methods: In vitro aggregation of α-synuclein in the absence or in the presence of SCFAs at a molar ratio of 1:1 or 1:4 α-synuclein:SCFA, were monitored by using independent assays: photo-induced cross-linking of unmodified proteins assay, thioflavin-T, fluorescence assay, or electron microscopy.

Results: We found that select microbiome-derived SCFAs significantly interfere with α-synuclein aggregation in independent in vitro assays.

Conclusions: Select microbiome-derived SCFAs may help protect against diverse synucleinopathies by converting dietary fibers into biologically available SCFAs which significantly interfere with aggregation of disease-specific αsynuclein into toxic aggregates. Ongoing cell-based systems, which detect levels of α-synuclein by florescent FRET signaling, will clarify the impact of this anti-aggregation activity of SCFAs on interference of α-synuclein seeding activity that is critical for the propagation of α-synuclein mediated pathologies. This data will help to clarify distinct α-synuclein seeding activity from α-synuclein isolated from post-mortem brain samples of patients with Parkinsonʼs disease, multiple systemic atrophies, and other synucleinopathies, leading to novel therapeutic approaches.

Biography:
Dr. Giulio Maria Pasinetti is the Saunders Family Chair and Professor of Neurology at the Icahn School of Medicine at Mount Sinai. He is the Program Director of the Center on Molecular Integrative Neuroresilience. The primary goal of the Center grant is understand the molecular mechanisms and pathophysiology that may be at the basis of stress-induced mood disorders, which are major risk factors for acceleration of age-related Alzheimerʼs disease and other forms of dementia. Dr. Pasinettiʼs Center is currently testing novel brain bioavailable bioactive “phytodrugs” that have been characterized by the Center in experimental models of disease in translational Alzheimerʼs disease preventative trials.

Neuroprotective Potential of Galantamine along with Coenzyme Q10 and Taurine against Aβ (1-42) Induced Cognitive Dysfunction: Involvement of Mitochondrial Dysfunction, Oxidative Damage, Neuroinflammation and Histopathological Alterations

Arti Singh^* and Anil Kumar

University Institute of Pharmaceutical Sciences, Panjab University, India

Taurine, 2-aminoethanesulfonic acid, acts as a neuromodulator, prevent mitochondrial dysfunction, apoptosis and oxidative stress. Coenzyme Q 10 (CoQ10), a lipophilic, endogenous, vitamin-like antioxidant compound. Galantamine, acetylcholinesterase inhibitors (AChEIs), is a novel treatment for AD and modulates nicotinic acetylcholine receptors (nAChRs). We aimed to evaluate the neuroprotective potential of taurine and CoQ10 along with galantamine in Aβ (1-42) induced cognitive dysfunction in rats. Intrahippocampal (i.h.) Aβ (1-42) (1µg/µl; 4µl/site) were administered, followed by drug treatment with taurine (25 and 50 mg/kg), CoQ10 (10 and 20 mg/kg), galantamine (2 mg/kg) and their combinations for a period of 21 days. Various neurobehavioral parameters followed by biochemical, AChEs level, mitochondrial enzyme complex level (I-IV), TNF-α level and histopathological alterations were assessed. Aβ (1-42) administration significantly impaired cognitive performance in Morris water maze (MWM) test, causes oxidative stress, raised AChEs level, neuroinflammation, mitochondrial dysfunction and histopathological alterations as compared to the sham treatment. Treatment with taurine (25 and 50 mg/kg), CoQ10 (10 and 20 mg/kg) and galantamine (2 mg/kg) improved cognitive performance in MWM test, reduced AChEs activity, neuroinflammation, oxidative damage, TNF-α level, restored mitochondrial respiratory enzyme complex (I-IV) activities and histopathological alterations as compared to Aβ (1-42) treated animals. Further, combinations of taurine (25 and 50 mg/kg) and CoQ10 (10 and 20 mg/kg) and their interaction with galantamine (2 mg/kg) significantly (P<0.05) modulate the neuroprotective potential of galantamine (2 mg/kg) as compared to their effect per se in Aβ (1-42) treated animals. The present study suggests the neuropotentiating effect of taurine and CoQ10 on galantamine in Aβ (1-42) treated animals.

Keywords: Alzheimerʼs disease, Aβ (1-42), CoQ10, taurine, galantamine, mitochondrial dysfunction, oxidative stress, neuroinflammation.

Early and Persistent O-GlcNAc Protein Modification in the Streptozotocin Model of Alzheimerʼs Disease

Carlos-Alberto Gonçalves^*, João Paulo Almeida dos Santos, Adriana Vizuete, Fernanda Hansen and Regina Biasibetti Universidade Federal do Rio Grande do Sul, Brazil O-GlcNActransferase (OGT), an enzyme highly expressed in brain tissue, catalyzes the addition of N-acetylglucosamine (GlcNAc) to hydroxyl residues of serine and threonine of proteins. Brain protein O-GlcNAcylation is diminished in Alzheimerʼs disease (AD), and OGT targets include proteins of the insulin-signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1). We hypothesized that ICV streptozotocin (STZ) also affects O-GlcNAc protein modification. We investigated hippocampal metabolic changes in Wistar rats, particularly OGT levels and insulin resistance, as well as related astroglial activities, immediately after ICV STZ administration (first week) and later on (fourth week). We found an early (at one week) and persistent (at fourth week) decrease in OGT in the STZ model of AD, characterized by a spatial cognitive deficit. Consistent with this observation, we observed a decrease in protein O-GlnNAc modification at both times. Increased phosphorylation at serine-307 of IRS-1, which is related to insulin resistance, was observed on the fourth week. The decrease in OGT and consequent protein O-GlnNAc modifications appear to precede the decrease in glucose uptake and increment of the glyoxalase system observed in the hippocampus. Changes in glial fibrillary acidic protein and S100B in the hippocampus, as well as the alterations in cerebrospinal fluid S100B, confirm the astrogliosis. Moreover, we found signs of astroglial dysfunction, which are likely implicated in the neurodegenerative cascade triggered in this model. Together, these data contribute to the understanding of neurochemical changes in the STZ model of AD, and may explain the decreases in protein O-GlcNAc levels and insulin resistance observed in AD.

Biography:
Carlos-Alberto Gonçalves is a medical doctor from Catholic University of Pelotas (Brazil, 1985), MSc and PhD in biochemistry from Federal University of Rio Grande do Sul (Brazil, 1992) and post-doctoral in neurochemistry from the University of Newcastle (Australia, 1995). He is full professor at Federal University of Rio Grande do Sul, working on programs of biochemistry and neuroscience. He is fellow researcher from National Council for Development of Science and Technology (CNPq) and honorary member of Cuban Society of Neuroimmunology. His basic and applied neurochemistry research focusing in: Activity, expression and secretion of S100B, a calcium-binding protein and Markers of glial activation in neurodegenerative diseases, particularly Alzheimer‘s disease.

Nose to Brain Delivery of Formulation by Design (FbD)- Enabled Quercetin Nanocarriers for Neurocognitive Disorders

Charan Singh^1* and Bhupinder Singh^1,2

¹University Institute of Pharmaceutical Sciences, Panjab University, India
²UGC—Centre of Excellence in Applications of Nanomaterials, Nanoparticles & Nanocomposites Biomedical Sciences, Panjab University, India

In the present study, Formulation by Design (FbD) enabled lipidic nanostructured system (NLCs) were formulated for quercetin. They were evaluated for their efficiency in nose-to-brain targeting and biodistribution in a suitable animal model after intranasal delivery. Further, particles size characterization revealed uniform shape with size less than 200 nm. Stability studies indicated refrigeration found to be the preferred storage condition. The intranasal delivery of quercetin nanoconstructs resulted in over 8 folds increase in relative brain vis-a-vis pure drug. The brain distribution studies of nanoconstructs exhibited significantly higher C_max (825.3±76 vs. 611.23 ±15 µg per gram of brain tissue), delayed T_max (4±1 vs.2± 0.5 h), prolonged T_1/2 (64.1±12 vs.12.62±1 h), MRT (36.80±2 vs. 6.93±0.5 h) and enhanced AUC_0-∞ (30914.33±113 vs. 3849.40±20 µg h/L) vis-a-vis pure quercetin. Moreover, biodistribution studies revealed lower quercetin concentration in the in non targeted tissues following intranasal delivery of nanoconstructs. Hence, the current investigation demonstrates the potential of nano-antioxidant as a potent therapeutic intervention for HIV associated neurocognitive disorders with improved biopharmaceutical attributes.

Brain Histamine and Forgetting: Possible Role in Aging

Edgardo O. Alvarez^1* and Silvia G. Ratti²

¹Laboratorio de Neuropsicofarmacología Experimental, Argentina
²Universidad Nacional de Cuyo, Argentina

Histamine, discovered at the beginning of the 20^th century is present in the brain in a specific and restricted region of the hypothalamus, the tuberomammillary nucleus. Composed of cluster of cells in a rather reduced number, project to various parts of the brain modulating several physiological functions. Our laboratory has shown previously in the rat that the imidazole amine is participating in learning and memory functions by specific modulation in the ventral hippocampus. Histaminergic neurons can inhibit the acquisition of a taskby activating an H_1^-Histamine receptor and inhibiting consolidation of the task by activating a H_2^- histamine receptor in hippocampal neurons. This evidence suggests that histamine neurons of the hypothalamus and its projections to hippocampus might be part of a regulatory brain circuit controlling acquisition, consolidation and evocation of memory information. Thus, if these neural processes are dysfunctional, it is possible to predict serious “loss” of memory. On this line,an increase in histamine levels in the brain of Alzheimer patients has been found, which might explain the memory disturbances usually associated with this disease, and supporting the concept that histaminergic neurons are part of a fundamental mechanism responsible of cognitive functions in mammals.

Biography:
Edgardo O. Alvarez born in 1944, in Iquique, Chile, he graduated in Physiology (Faculty of Sciences, Universidad Austral de Chile, Valdivia, Chile). He was assistant professor and later Director of the Institute of Physiology, School of Medicine, Universidad Austral de Chile. From 1969 to 1982 his main line of research was the neuroendocrinology of puberty. Later in 1983 he moved to the Faculty of Medical Sciences, Universidad Nacional deCuyo, Mendoza, Argentina, where he got the position of assistant professor and career researcher in CONICET. From there on he studied the biological role of histamine on cognitive functions of the brain.

“FDA-Approved Drug ITB Regulates LPS-Induced Neuroinflammation through AKT/STAT3 Signaling Pathways”

Hyang-Sook Hoe

Korea Brain Research Institute, Republic of Korea

Neuroinflammation plays a key role in its pathogenesis with the activation of microglia and the secretion of proinflammatory cytokines causing neurodegenerative disorders. As an FDA-approved drug, small molecule ITB is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Brutonʼs tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. However, it remains unknown whether ITB can regulates neuroinflammation. Thus, we examined the effects of ITB on LPS-mediated neuroinflammatory response in BV-2 microglial cells and found that ITB reduced LPS-induced proinflammatory cytokine levels. In addition, ITB suppressed LPS-mediated pro-inflammatory cytokine levels by inhibiting Toll-like receptor 4 (TLR4) receptor. ITB significantly decreased LPS-induced p-AKT levels and treatment with AKT inhibitor, ITB, and LPS further reduced pro-inflammatory cytokine levels in comparison with treatment with AKT inhibitor and LPS. These data suggest that ITB modulates LPS-induced proinflammatory cytokine levels via AKT signaling. Moreover, ITB significantly reduced LPS-mediated transcription factor STAT3 translocation to the nucleus. These results demonstrate that ITB attenuate LPS-induced neuroinflamatory response by inhibiting AKT and STAT3 signaling pathways.

Biography:
Dr. Hyang-Sook Hoeʼs research is focused on the role of APP and its binding synaptic proteins in the neuronal and synaptic damage that occurs with select neurodegenerative diseases of the central nervous system (CNS). In addition, his laboratory is focus on develop the potential drugs for Alzheimerʼs disease (AD). One novel strategy to overcome AD pathology is the use of small molecules to prevent aggregated Aβ from interacting with cellular components in harmful ways. In addition to this, we currently have 15 of these novel agents, which can act anti-inflammatory drug. To achieve our goals, he will continuously examine the effectiveness of Aβ targeting small chemicals and 15 of these novel agents as effective novel therapeutic strategy for AD.

Dementia with Lewy Bodies Psychopathology and Evidence Based Management

Vinodkumar Gangolli^1* and Leena Vinod Gangolli²

¹McMasterʼs University, Canada
²Independent Palliative Care Consultant, India

Dementia with Lewy bodies is an under-recognized disease; it is responsible for up to 20% of all dementia cases. Accurate diagnosis is essential because the management of dementia with Lewy bodies is more complex. Alpha-synuclein, the pathological protein responsible for dementia with Lewy bodies (and Parkinsonʼs disease), produces symptoms in multiple domains. A comprehensive treatment strategy can be achieved by treating core clinical features such as cognitive, neuropsychiatric, movement, autonomic, and sleep categories. Invariably the treatment of one set of symptoms can cause complications in other symptom domains, but a comprehensive treatment program can greatly improve the patientʼs quality of life, but does not alter the progression of disease. Cholinesterase inhibitors are effective for cognitive and neuropsychiatric symptoms; Special care needs to be taken to avoid potentially fatal idiopathic reactions to neuroleptic medications; these should be used for short periods only when absolutely necessary and when alternative treatments have failed. Pimavanserin, a selective serotonin 5-HT2A inverse agonist, holds promise as an alternative therapy for synuclein-associated psychosis. Levodopa/carbidopa treatment of Parkinsonism is often limited by dopa-induced exacerbations of neuropsychiatric and cognitive symptoms. Autonomic symptoms are under-recognized complications of synucleinopathy. Constipation, urinary symptoms and postural hypotension respond to standard medications. Rapid eye movement sleep behavior disorder is highly specific (98%) to the synucleinopathies. Non-pharmacological treatments, melatonin and clonazepam are all effective.

Biography:
Dr. Vinodkumar Gangolli is a Fellow of the Royal College of Physicians and Surgeons of Canada, a Member of the Royal College of Psychiatrists, London, England, and is Board certified in Psychiatry and Geriatric Psychiatry by the American Board of Psychiatry and Neurology, Chicago, USA. He holds the post of Assistant Clinical Professor of Psychiatry (adjunct), in the Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada. He is also a Consultant Psychiatrist in the Department of Psychiatry, Grand River Hospital Corp., Kitchener, Ontario, Canada and Dean of Academics at Masina Hospital, Byculla, Mumbai, India. He is a member of WHO ICD-11 Consultation group of Mental and Behavioral Disorders in Older Adults, Geneva, Switzerland.

C9 or f72 poly GA RAN-Translated Protein Plays a Key Role in Amyotrophic Lateral Sclerosis via Aggregation and Toxicity

Youn-Bok Lee^1*, Pranetha Baskaran², Jorge Gomez¹, Han-Jou Chen¹, Agnes Nishimura¹, Bradley Smith¹, Claire Troakes¹, Yoshitsugu Adachi¹, Alan Stepto¹, Leonard Petrucelli⁴, Jean-Marc Gallo¹, Frank Hirth¹, Boris Rogelj³, Sarah Guthrie² and Christopher E Shaw¹

¹United Kingdom Dementia Research Institute Centre, Kingʼs College London, United Kingdom
²Department of Developmental Neurobiology, Kingʼs College London, UK
³Department of Biotechnology, Jožef Stefan Institute, Slovenia
⁴Department of Neuroscience, Mayo Clinic Florida, USA

An intronicGGGGCC (G4C2) hexanucleotide repeat expansion in C9 or f72 is the most common genetic cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (C9ALS/FTD). Repeat-associatednon-AUG (RAN) translation of G4C2 RNA can result in five different dipeptide repeatproteins (DPR: poly GA, poly GP, poly GR, poly PA, and poly PR), which aggregate into neuronal cytoplasmic and nuclear inclusions in affected patients, however their contribution to disease pathogenesis remains controversial. We show that among the DPR proteins, expression of poly GA in a cell culture model activates programmed cell death and TDP-43 cleavage in a dose-dependent manner. Dual expression of poly GA together with other DPRs revealed that poly GP and poly PA are sequestered by poly GA, whereas poly GR and poly PR are rarely co-localised with poly GA. Dual expression of poly GA and poly PA ameliorated poly GA toxicity by inhibiting poly GA aggregation both in vitro and in vivo in the chick embryonic spinal cord. Expression of alternative codon-derived DPRs in chick embryonic spinal cord confirmed in vitro data, revealing that each of the dipeptides caused toxicity, with poly GA being the most toxic. Further, in vivo expression of G4C2 repeats of varying length caused apoptotic cell death, but failed to generate DPRs. Together these data demonstrate that C9-related toxicity can be mediated by either RNA or DPRs. Moreover, our findings provide evidence that poly GA is a key mediator of cytotoxicity and that cross-talk between DPR proteins likely modifies their pathogenic status in C9ALS/FTD.

Biography:
Younbok Lee obtained her PhD in Molecular Neuroscience from University of Bristol (UK), in 2006, where he pursued a Three-year postdoctoral project. He discovered that the transcription factor Twist 1 is responsible for the direct regulation of microRNA 241-199 clusters, which is region specifically regulated for embryogenesis (Nucleic acid research, 2009). Then he moved to the Clinical Neuroscience in Kings College London in 2010 where he identified toxicity of the RNA foci of hexanucleotide expansion from C9 or f72 (Cell Reports, 2013). Currently he is working on molecular mechanism of noncoding RNA and binding proteins, which are responsible for ALS/FTLD.