Madridge Journal of Behavioral & Social Sciences

ISSN: 2638-2032

International Conference on Alzheimer Disease & Associated Disorders

May 7-9, 2018, Rome, Italy
Scientific Session Abstracts
DOI: 10.18689/2638-2032.a1.002

Neurovascular Pathology in ApoB-100 Transgenic Mice

Melinda E. Tóth1*, Zsófia Hoyk2, Ágnes Kittel3, Mária A. Deli2 and Miklós Sántha1

1Institute of Biochemistry, Biological Research Centre, Hungary
2Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Hungary
3Institute of Experimental Medicine, Hungarian Academy of Sciences, Hungary

Apolipoprotein B-100 (ApoB-100) is the major protein component of the low density and very-low-density lipoproteins that are responsible for cholesterol and triglyceride transport from the liver to the peripheral tissues. Therefore, the ApoB-100 overexpressing mouse strain is a frequently used model of atherosclerosis, as they are more susceptible to the cholesterol-enriched diet induced myocardial dysfunction. Moreover, previously we detected widespread neurodegeneration, neuronal apoptosis, synaptic dysfunction and tau-hyperphosphorylation in the brain of ApoB-100 transgenic mice finally leading to cognitive impairment. Since the neurovascular origin of various neurodegenerative diseases is becoming more and more accepted, our aim was to study the structural and functional impairments of the blood-brain barrier in ApoB-100 transgenic mice. In vivo permeability studies showed increased blood-brain barrier permeability in the hippocampus, while the disruption of the brain capillary endothelial tight junction structure and edematous swelling of astrocyte end-feet were demonstrated using transmission electron microscopy in transgenic brains. We found decreased P-glycoprotein (Abcb1) and vimentin immunostainings and altered Gfap immunostaining pattern related to the neurovascular unit by confocal microscopy. Real-time PCR showed increased Lox-1, Aqp4, and decreased Meox-2, Mfsd2a, Abcb1a, Lrp2, Glut-1, Nos2, Nos3 gene expression level in isolated microcapillary fraction of transgenic mice. These results underline the neurovascular origin of neurodegeneration in hypertriglyceridemicApoB-100 transgenic mice.

Acknowledgment: This study was supported by the Hungarian Scientific Research Fund – OTKA (OTKA NN- 111006) and NRDI Office Hungary (GINOP-2.3.2-15-2016-00060).

Melinda E. Tóth is currently a research associate scientist in the Institute of Biochemistry of the Biological Research Centre (Szeged, Hungary). She graduated from the University of Szeged with a master degree in biology in 2006. After graduation she continued her work in the lab of MiklósSántha, the Laboratory of Animal Genetics and Molecular Neurobiology as a PhD student and got her PhD from the University of Szeged in 2013. Her research interest is investigating the molecular basis of the protective role of heat shock proteins in diseases like Alzheimerʼs disease and hyperlipidemia induced neurodegeneration in transgenic mouse models.

MRI Lateralization Index of Hippocampal Subfields Could Characterize Progression of Mild Cognitive Impairment to Alzheimerʼs Disease

Alessia Sarica1*, Roberta Vasta1, Fabiana Novellino2 and Aldo Quattrone2,3

1Neuroscience Research Center, Magna Graecia University of Catanzaro, Italy
2Institute of Bioimaging and Molecular Physiology (IBFM), Italy
3Institute of Neurology, University Magna Graecia of Catanzaro, Italy

A plethora of neuroimaging studies reported significant asymmetry of hippocampus in Alzheimerʼs disease (AD), indicating that difference in volumes between left and right exists and varies with disease progression. However, few works investigated whether asymmetries of hippocampi could characterize the conversion of Mild Cognitive Impairment (MCI) to AD. Thus, aim of the present work was to evaluate the Lateralization Index (LI) of hippocampal substructures as MRI biomarker for differentiating stable (sMCI) from progressive MCI (pMCI). Two-hundred subjects were selected from ADNI, 100 sMCI (72.2 yrs, MMSE 28) and 100 pMCI (72.4 yrs, MMSE 27.3). The structural baseline T1s were processed with FreeSurfer 6.0 and volumes of hippocampi+12 subfields were extracted. Paired t-test was used for assessing significant differences between left and right, separately for sMCI and pMCI. The LI was calculated as the absolute value of: ((Left-Right)/(Left+Right))*100. ANOVA adjusted for age, gender and intracranial volume was used for evaluating significant LI differences between sMCI and pMCI. The statistical threshold was Bonferroni corrected p<0.05/13=0.0038. Both sMCI and pMCI had rightward asymmetries (right>left) in WH, CA1, CA3, CA4, GC_ML_DG, tail and HATA, and leftward (left>right) in presubiculum, while a rightward was found only in fissure and molecular layer of sMCI. The magnitude of LI was about 50% higher in pMCI than sMCI in the WH, subiculum and molecular layer. These preliminary findings showed that hippocampal LI may be an early biomarker and that patients with stronger degree of asymmetry in these substructures had an increased risk of converting into AD.

Alessia Sarica is currently a Post-doc Research-Fellow at Neuroscience Research Center, Department of Medical and Surgical Sciences, Magna-Graecia University of Catanzaro, Italy. She ownsa PhD in Biomedical and Computer Science Engineering and her research interests are on knowledge discovery from Neuroimaging, pattern-recognition and machine-learning. She has wide expertise in Random Forest and presented a systematic review about it for the prediction of Dementia (Sarica et al., 2017). She was the organizer and Special Guest Editor of a special issue on Journal of Neuroscience Methods:“A Machine learning neuroimaging challenge for automated diagnosis of Mild Cognitive Impairment” (Sarica et al., 2018).

Amyloid-β Oligomers, Neuroinflammation and Novel Targets for Alzheimerʼs Disease

Michael Harte

University of Manchester, United Kingdom

With current treatments for Alzheimerʼs disease (AD) only providing temporary symptomatic benefits disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD.

A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. In support of this we have previously demonstrated the effects of an acute administration of LMW Aβo (SynAging) on cognitive, inflammatory, synaptic and neuronal markers in the rat [Watremez et al., 2018 Journal of Alzheimerʼs Disease]. This model is very well established in our lab, is robust, reproducible and gives a measurable cognitive end point within 2 weeks. We have utilised this model for assessing symptomatic and/or neuroprotective effects of disease modifying drug candidates.

It is becoming apparent that one such target, inflammation, is a key contributor to the progression of AD. In particular, on-going research is establishing the NLRP3-inflammasome complex as one of the most important regulators of inflammation, and that NLRP3 is central to the development of inflammation, pathology and memory deficits in rodent models for AD research. Our data point toward the NLRP3 inflammasome as a novel therapeutic target for AD.

Michael Harte is a neuropharmacology researcher currently working in the Division of Pharmacy & Optometry at the University of Manchester as a Senior Lecturer in Drug Action. Her lab specialises in the development of preclinical models of neuropsychiatric and neurodegenerative disorders for the testing of novel compounds for progression to the clinic. Her overall research goal is to develop improved preclinical models to advance our understanding of different CNS diseases and aid in the identification and testing of novel targets to ultimately improve treatment for patients.

Prediction of Conversion to Alzheimerʼs Disease in Individuals with Mild and Premild Cognitive Impairment with Machine Learning Algorithms

Massimiliano Grassi1*, David A. Loewenstein2,3,4, Daniela Caldirola1, Koen Schruers5, Ranjan Duara2,3,7 and Giampaolo Perna1,2,5,8

1Department of Clinical Neurosciences, Villa San Benedetto Menni Hospital, Italy
2Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, USA
3Wien Center for Alzheimerʼs Disease and Memory Disorders, Mount Sinai Medical Center, USA
4Center on Aging, Miller School of Medicine, University of Miami, USA
5Research Institute of Mental Health and Neuroscience and Department of Psychiatry and Neuropsychology, University of Maastricht, Netherlands
6Department of Neurology, Herbert Wertheim College of Medicine, Florida International University, USA
7Department of Neurology, University of Florida College of Medicine, USA
8Mantovani Foundation, Arconate, Italy

No cure for Alzheimerʼs Disease (AD) has been found yet. Early identification of which subjects at high risk, i.e. those with Mild Cognitive Impairment (MCI), will later develop AD is of key importance. This would allow making clinical trials of new AD treatments more cost-effective and valid, as well as beginning available therapies at an early stage of the disease progression. Several machine learning algorithms for the prediction of conversion to AD in subjects with MCI have been proposed. However, most of them either achieved only limited predictive accuracy or are based on expensive and hard-to-collect information. A novel algorithm for a prediction of a 3-year conversion to AD in MCI and PreMCI subjects will be presented. The prediction is based only on cost-effective and non-invasively collectable information, such as sociodemographic characteristics, neuropsychiatric and neuropsychological test scores, cardiovascular risk indexes, and clinician rated levels of brain atrophy. The algorithm was trained on a sample of 123 MCI/PreMCI subjects and achieved a cross-validated AUC of 0.962 and a balanced accuracy of 0.913 (MCI sub-group alone: AUC = 0.914, balanced accuracy = 0.874). An indirect evidence of its generalized accuracy obtained with a transfer learning approach will be also presented. In conclusion, our algorithm achieved very high performances out performing the vast majority of currently available algorithms although it only employs predictors which can be non-invasively and cost-effectively assessed. Further testing and optimization in independent samples will finally warrant its trusted application in both clinical trials and clinical practice.

Massimiliano Grassi is senior data and research scientist at the Clinical Neurosciences Department of Villa San Benedetto Menni Hospital (Albese con Cassano, Como, Italy), cognitive psychoterapist and lecturer in statistics at the Istituto Superiore di Osteopatia (Milan, Italy). He is author of more than 15 scientific papers and his current research interest focuses on the application of machine learning techniques for the development of predictive algorithms and personalized medicine tools in field of the dementia and psychiatric disorders.

Modulation of Beta-Amyloid Peptide Transporters on Brain-Blood Barrier by Ketogenic Diet

Rita Businaro1*, Corsi Mariangela1,2, Versele Romain2, Fuso Andrea3, Sevin Emmanuel2, Di Lorenzo Cherubino4, Fenart Laurence2, Alessandro Pinto5, Gosselet Fabien2 and Candela Pietra2

1Sapienza University of Rome, Dept. of Medico-Surgical Sciences and Biotechnologies, Italy
2Univ. Artois, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), France
3Sapienza University of Rome, Dept. of Surgery “P. Valdoni”, Italy
4Don Carlo Gnocchi Onlus Foundation, Italy
5Sapienza University of Rome, Dept. of Experimental Medicine, Italy

Given the current absence of an effective pharmacologic treatment for Alzheimerʼs disease (AD), the development of alternative therapeutic approaches (such as the ketogenic diet, KD) might be considered. The KD is a low-carbohydrate, high-fat diet based on the production of ketone bodies (KBs) in the blood. In view of the KDʼs beneficial effects on the central nervous system and the lack of published data on the blood brain barrier (BBB), we used an in vivo/in vitro approach to investigate the effect of the KD and KBs on the BBB. For the in vivo study, blood from 129Sv mice was assayed for beta-hydroxybutyrate and glucose dosage. Brain capillaries were isolated from mouse cortices, and RT-qPCR assays were used to evaluate the mRNA expression of transporters/receptors involved in the synthesis and transport of KBs, glucose and amyloid-beta (Aβ) peptide. The mRNA assays were also performed in an in vitro BBB model, based on brain-like endothelial cells (BLECs). After a ketotic state had been established and the BLECsʼ integrity had been confirmed, we evaluated the mRNA expression of KB-, glucose- and Aβ-related genes. Lastly, the transport of fluorescently labelled Aβ-peptide across the BBB was studied after treatment with KBs. Our results showed that KBs regulate the expression of certain Aβ-peptide transporters/receptors and amyloid peptide-synthesizing enzymes. These data suggest that it is possible to modulate key molecular players in Aβ-peptide transport and synthesis at the BBB, and thus open up new perspectives for studying KB-related therapeutic approaches.

Rita Businaro, MD, PhD is a Professor of Human Anatomy in Faculty of Pharmacy and Medicine at Sapienza University of Rome, Italy. She is a Director of the II level Master in “Stress, Sport, Nutrition: New Diagnostic and Therapeutics Tools for Wellness, Fitness and Rehabilitation”. She is Vice-president of AIF (Italian Fulbright Association) and Member of ISNIM (International Society for NeuroimmunoModulation). She is also Coordinator of Erasmus Plus program. His main research topics is Study of comorbidity of Alzheimerʼs disease and cerebrovascular disorders: a multidisciplinary approach to identify cellular proteins and mechanisms involved in the accumulation of amyloid aggregates in the central nervous system, Cross-talk Central Nervous System-Immune System and Diet role in delaying Alzheimerʼs disease progression.

On the Role of APP in Acute (Stroke, Neurotrauma) and Chronic (Alzheimerʼs Disease) Neurodegeneration

Anatoly Uzdensky* and Svetlana Demyanenko

Southern Federal University, Russia

Accumulation of beta-amyloid (Aβ) in the brain cortex due to proteolysis of amyloid precursor protein (APP) leads to chronic neurodegeneration in Alzheimerʼs disease. APP overexpression is also involved in pathophysiology of acute brain damage such as neurotrauma and ischemic stroke. We used protein microarrays to study changes in expression of signaling and neuronal proteins in the penumbra (2-mm ring around the infarction core) 1-24 hours after photothrombotic stroke in the rat brain cortex (ischemic stroke model). Among other biochemical changes (overexpression of pro- and antiapoptotic proteins, signaling proteins, actin cytoskeleton elements, and downregulation of tubulin and cytokeratins, and proteins involved in vesicular transport and synaptic processes), we observed overexpression of APP; nicastrin (component of γ-secretase); Aβ fragment (13-28); LRP1 (APOE receptor) and TMP21 that regulate APP proteolysis and Aβ release. Therefore, APP is rapidly accumulated and processed and in penumbra after acute brain damage. APP is also known to accumulate in injured nerves. We hypothesize the functional, probably, protective role of APP in dying neurons. In different pathogenic situations Intracellular APP fragment AICD can release and function as a transcription factor to regulate the expression of APP and other proteins. In chronic diseases such as Alzheimerʼs disease death of individual neurons can occur similarly during few hours. Aβ release may be not harmful during short time intervals, but its aggregation can delay or prevent proteolysis and lead to Aβ accumulation, formation of amyloid plaques and neurodegeneration for years and dozens of years.

Anatoly B. Uzdensky is a professor and a head of the Laboratory of Molecular Neurobiology at the Southern Federal University (Rostov-on-Don, Russia). He is the author of more than 120 journal papers and 3 books. His current research interests include stroke and neurotrauma, neurodegeneration and neuroprotection, cell biology, cell signaling and proteomics.

Why Physical Exercise is the Best Way to Rejuvenate Ageing Brains?

Sonata Yau

Hong Kong Polytechnic University, Hong Kong

With the rapid increase in the ageing population worldwide, tackling brain ageing is one of the most challenging contemporary health issues. Despite the huge long-term investment in the search for drugs that can delay or prevent aging-associated cognitive decline, the currently available pharmaceutical treatments are only modestly effective. The human brain possesses remarkable neuroplasticity (which refers to the brainʼs ability to reorganize its structure and function in response to environmental stimulation), even later in life. Physical exercise is known to be the best medicine to improve brain health throughout an individualʼs lifespan. Higher levels of physical activity are associated with better brain function, such as improved cognition learning and memory performance, especially in aged brains, suggesting physical exercise could be a non-pharmacological intervention for boosting capability of brain plasticity. In this talk, I will highlight the beneficial effects of physical exercise on promoting neuroplasticity in the hippocampus, a brain important for learning and memory and emotion regulation. I will also introduce the latest discoveries in animal research reporting the biological basis in which physical exercise influences hippocampal function, which is linked to cognitive and neuropsychiatric disorders, such as depression.

Dr. Sonata Yau obtained her Bachelor degree in Biochemistry from the Hong Kong University of Science and Technology in 2005, followed by a PhD in neuroscience in Department of Anatomy at the University of Hong Kong in 2009. She was awarded with several postdoctoral fellowships, research fellowships, conference travel awards and outstanding presentation awards. Before joining the Department of Rehabilitation Sciences, Hong Kong Polytechnic University, she worked as a postdoctoral fellow in the Division of Medical Sciences, University of Victoria, Canada. She is interested in studying the neural basis of pharmacological and non-pharmacological interventions that promote brain function in different disease animal models.

Age-and Gender-Linked Differences in MRI Lateralization Index of Hippocampal Subfields

Alessia Sarica1*, Roberta Vasta1, Fabiana Novellino2 and Aldo Quattrone2,3

1Neuroscience Research Center, Magna Graecia University of Catanzaro, Italy
2Institute of Bioimaging and Molecular Physiology (IBFM), Italy
3Institute of Neurology, University Magna Graecia of Catanzaro, Italy

Asymmetry of hippocampus is relevant in neurological diseases, however asymmetry of its substructures is poorly investigated in general population, and few is known about the normal-aging variations. For this reason, we explored differences in laterality index (LI) between females and males, and the correlation of LI subfields with age. One-hundred healthy subjects were selected from ADNI, 52 females (72.6 yrs) and 48 males (age 74.2 yrs). The structural baseline T1s were processed with Free Surfer 6.0 and volumes of hippocampi and 12 subfields were extracted. Paired t-test was used for assessing differences in left and right, separately for females and males. The LI was calculated as absolute value of:((Left-Right)/(Left+Right))*100. ANOVA adjusted for age and intracranial volume (ICV) was used for evaluating LI differences between groups. The correlation between age and LIs was investigated by linear regression with ICV as covariate. The statistical threshold was Bonferroni corrected p<0.05/13=0.0038. Both females and males had rightward asymmetries (right>left) in WH, CA1, CA3, CA4, GC_ML_DG, molecular layer, tail and HATA, while a leftward asymmetry (left>right) was found only in presubiculum of males. Males had higher asymmetry degree than females in parasubiculum (+30%) and tail (+20%), even if differences did not survive at Bonferroniʼs. Only males presented association survived at Bonferroniʼs between age and LI of WH, molecular layer and tail. Our findings showed that males had higher asymmetry magnitude than females, which increases with normal aging and we suggest that age and sex should be considered when evaluating hippocampal subfields laterality, especially when pathologies are studied.

Alessia Sarica is currently a Post-doc Research-Fellow at Neuroscience Research Center, Department of Medical and Surgical Sciences, Magna-Graecia University of Catanzaro, Italy. She ownsa PhD in Biomedical and Computer Science Engineering and her research interests are on knowledge discovery from Neuroimaging, pattern-recognition and machine-learning. She has wide expertise in Random Forest and presented a systematic review about it for the prediction of Dementia (Sarica et al., 2017). She was the organizer and Special Guest Editor of a special issue on Journal of Neuroscience Methods:“A Machine learning neuroimaging challenge for automated diagnosis of Mild Cognitive Impairment” (Sarica et al., 2018).

PSEN1 Expression is Associated to Promoter Methylation in the Brain of Alzheimerʼs Mice and in Humans

Andrea Fuso

Sapienza University of Rome, Italy

Presenilin1 (PSEN1) protein constitutes the catalytic subunit of the γ-secretase complex. This enzyme, among other, is responsible for the processing of the amyloid βprotein precursor (AβPP), eventually leading to the production and accumulation of the amyloid β (Aβ) peptides in the brain, associated with the Alzheimerʼs Disease (AD). PSEN1 and γ-secretase are also responsible for the processing of key molecules (E-cadherin, Notch1) in course of neurodevelopment.

Depicting the regulation of PSEN1 could be useful for the comprehension of the molecular mechanisms underlying neurodevelopment and neurodegeneration. Previous studies indicated PSEN1 as a locus subject to differential methylation in Alzheimerʼs Disease affected subjects versus healthy controls. Moreover, we previously demonstrated that PSEN1 methylation and, consequently, expression are modulated by perturbation of the methylation metabolism in AD mice.

The present study allowed to characterize the DNA methylation profile of PSEN1 promoter during the neurodevelopment and neurodegeneration, in the frontal cortex of TgCRND8 AD transgenic mice and of human subjects. The data obtained, allowed to demonstrate that both CpG and non-CpG (CpA, CpC, CpT) methylation of PSEN1 promoter is differentially modulated during development and aging and in AD patients versus controls. PSEN1 expression was correlated to CpG and non-CpG methylation patters. Altogether, these data point-out that non-CpG methylation has a functional role in PSEN1 regulation and stress the hypothesis that AD may have an epigenetic basis.

Andrea Fuso, Ph.D., biologist, is researcher at Sapienza University of Rome. He teaches at post-graduations courses and is author of several scientific papers, book chapters and is speaker at many lectures and conferences. He serves in editorial boards, as referee for journals and grant committees and in the Board of Directors of the Epigenetics Society.
His researches focus on neurodegenerative diseases, one-carbon metabolism and methylation reactions, studying the dynamics of DNA methylation/demethylation and then on-CpG methylation, applied to nutrition and one-carbon metabolism in neurodegeneration and muscle differentiation.

Presenilin1 FAD Mutations Inhibit Neovascularization and Increase Vulnerability of Brain to Ischemia

Anastosios Georgakopoulos*, Yoon Y, Voloudakis G, Doran N and Robakis N.K

Icahn School of Medicine at Mount Sinai, USA

A large amount of evidence has linked brain vascular disorders to the onset of Alzheimerʼs disease (AD). AD brains show impaired brain vasculature with changes in the microvasculature preceding neurodegenerative changes and cognitive decline. The changes in vasculature can be caused by a variety of factors including decreased angiogenesis. Insufficient angiogenesis and vascular regression in the AD brain may represent an important pathogenic mechanism ultimately affecting neuronal health.

We observed that Presenilin1 (PS1) a protein involved in the pathogenesis of familial AD (FAD) promotes the angiogenic response of endothelial cells in vitro and that mutants of PS1 linked to FAD inhibit this function. We also found that a PS1 FAD mutant impairs brain neovascularisation after ischemic insult, a toxic stress known to induce angiogenesis, and that this mutant increases neuronal death induced by ischemia. MCAO-induced neovascularization, cerebral blood flow (CBF) and neuronal survival as measured by Collagen-IV immunostaining, perfusion MRI and NeuN immunostaining respectively were significantly decreased in FAD brains compared to WT. In addition VE-cadherin/Rok-α/Raf-1 angiogenic complexes, which regulate angiogenesis and which we have found to depend on PS1/γ-secretase, were decreased in brain extracts of PS1 FAD mutant mice compared to WT controls suggesting that PS1 regulates this angiogenic pathway in vivo and that PS1 FAD mutants impair brain angiogenesis.

Together our data indicate that in FAD, brain vasculature is compromised due to defective angiogenesis, rendering the brain more vulnerable to toxic insults with reduced ability to recover leading to increased cell death and neurodegeneration.

Anastosios Georgakopoulos is a Research Associate Professor at the Center for Molecular Biology and Genetics of Neurodegeneration, department of Psychiatry at Icahn School of Medicine at Mount Sinai. Her laboratory studies mechanisms of ephrinB/EphB-mediated angiogenesis and neuroprotection and the role that Presenilin1/γ-secretase system has on their regulation aiming to discover methods to treat and prevent neurodegenerative disorders like AD. He had been working on the molecular biology of Presenilin1 for 20 years. He found the interaction of Presenilin1 with substrates of γ-secretase such as E- and N-cadherins, ephinB ligands and EphB receptors and the physiological role that these interactions may have.

The Expression and Activity of KV3.4 Channel Subunits are Precociously Upregulated in Astrocytes Exposed to Aβ Oligomers and in Astrocytes of Alzheimerʼs Disease Tg2576 Mice

Anna Pannaccione1*, Roselia Ciccone1, Francesca Boscia1, Ilaria Piccialli1, Antonella Casamassa1, Cristina Franco1, Valeria de Rosa1, Antonio Vinciguerra1, Adolfo Sadile2, Gianfranco Di Renzo1 and Lucio Annunziato1

1Department of Neuroscience, Reproductive and Odontostomatological Sciences,”Federico II” University of Naples, Italy
2Department of Experimental Medicine, II University of Naples, Italy

Astrocyte dysfunction emerges early in Alzheimerʼs disease (AD) and may contribute to its pathology and progression. Recently, the voltage gated potassium channel KV3.4 subunit, which underlies the fast-inactivating K+ currents, has been recognized to be relevant for AD pathogenesis and is emerging as a new target candidate for AD. In the present study, we investigated both in in vitro and in vivo models of AD the expression and functional activity of KV3.4 potassium channel subunits in astrocytes. In primary astrocytes biochemical, immunohistochemical, and electrophysiological studies demonstrated a time-dependent upregulation of KV3.4 expression and functional activity after exposure to amyloid-β (Aβ) oligomers. Consistently, astrocytic KV3.4 expression was upregulated in the cerebral cortex, hippocampus, and cerebellum of 6-month-old Tg2576 mice. Further, confocal triple labeling studies revealed that in 6-month-old Tg2576 mice, KV3.4 was intensely coexpressed with Aβ in nonplaque associated astrocytes. Interestingly, in the cortical and hippocampal regions of 12-month-old Tg2576 mice, plaque-associated astrocytes much more intensely expressed KV3.4 subunits, but not Aβ. More important, we evidenced that the selective knockdown of KV3.4 expression significantly downregulated both glial fibrillary acidic protein levels and Aβ trimers in the brain of 6-month-old Tg2576 mice. Collectively, our results demonstrate that the expression and function of KV3.4 channel subunits are precociously upregulated in cultured astrocytes exposed to Aβ oligomers and in reactive astrocytes of AD Tg2576 mice.

Anna Pannaccione is the assistant Professor of Pharmacology at the Department of Neuroscience of the University of Naples Federico II, School of Medicine from 2004.
His main research themes are focused on the functional, pathophysiological and pharmacological role(s) of diverse classes of ionic channels and transporters. Throughout the years, these themes have been pursued by means of an integrated approach using electrophysiological, biochemical, genetic, and pharmacological techniques. In particular, the following research themes have been addressed to the characterization of the involvement of ionic homeostasis dysregulation in Alzheimerʼs disease with particular attention to the study of sodium/calcium exchanger, voltage-gated potassium KV3.4/mirp2, and sodium NaV1.6 channels.

Retinal Imaging of Misfolded Proteins in Alzheimerʼs

Umur Kayabasi

Uskudar University, Turkey

Introduction: Tau protein plays a crucial role in many neurodegenerative diseases including Alzheimerʼs disease (AD). Tau inclusions and amyloid beta (AB) depositions have been described in the post-mortem retina exams of AD patients. Cryo-electron microscopy (Cryo-EM) was recently used to detect the detailed structure of Tau filaments.

Methods and Result: We examined the retinas of PET-proven live AD patients by spectral domain optical scanning tomography (SD-OCT) and fundusau to fluorescein (FAF). The hyper or hypo-fluorescent lesions in the retina were scanned by OCT and images that completely corresponded with the histopathological and Cryo-EM shapes of Tau filaments were observed.

Conclusion: Retinal Tau is a very promising target to detect early changes in AD and retinal imaging may be an exciting and trust able technique to predict and monitor the disease.

Umur Kayabasi is a graduate of Istanbul Medical Faculty. After working as a resident in Ophthalmology, he completed his clinical fellowship program of Neuroophthalmology and Electrophysiology at Michigan State University in 1995. After working as a consultant neuro-ophthalmologist in Istanbul, he worked at Wills Eye Hospital for 3 months as an observer. He has been working at World Eye Hospital since 2000. He has chapters in different neuro-ophthalmology books, arranged international symposiums, attended TV programs to advertise the neuro-ophthalmology subspecialty. He has also given lectures at local and international meetings, plus published many papers in neuro-ophthalmology. He became an Assistant Professor at Uskudar University/Istanbul in 2016.

Nuclear Envelope and Nuclear Pore Complex in Oxidative Stress, Aging and Neurodegeneration

Jerzy Leszek

Wroclaw Medical University, Poland

The majority of enzymes and their substrates engaged in cellsʼ proliferation, differentiation and other vital functions shuttled between intranuclear and cytosolic compartments through the nuclear pore complexes, aqueous channels formed by multicomponent protein complexes of the nuclear envelope, also called nucleoporins. The nuclear pore protein complexes regulate movement of cell components from cytosol to nucleus and vice versa. Defective nucleoporin function could lead to inappropriate localization of a large number of nuclear and cellular components.

Nucleoporin composition and structure are significantly age-dependent and cells lose essential nucleopore proteins with age. Oxidative stress applied to cells in culture caused marked changes in phosphorylation and 0-glycosylation of nucleoporin proteins, and altered their localization and interaction with other transport components, Such changes of the nuclear pore complex structure and function cold lead to aberrant intracellular trafficking of cell cycle regulating proteins and signaling proteins.

Currently, growing body of evidence (and our seech) reveals that disturbances of nucleoporin structure and function are regular feature of degenerating neurons and could be responsible, in a major part, for the patho mechanism of neurodegeneration.

Dr Jerzy Leszek is Professor of Psychiatry, Vice-Head of the Department of Psychiatry, Head of Alzheimerʼs Disease Lab at the Medical University in Wroclaw, and Scientific Director of Alzheimerʼs Disease Center in Scinawa near Wroclaw, Poland. He graduated at Medical University of Wroclaw in 1979, was awarded a doctorate in Wroclaw in 1981 and in 1999- examination for the degree of associate professor of psychiatry and since 2005 he is working as full professor of psychiatry at Wroclaw Medical University. He is author and co-author more than 250 papers (especially from old age psychiatry), some chapters to the books published in reputed Polish and international journals and serving as an editorial board member of several journals. He is Editor –in-Chief of Journal of Yoga and Physical Activity. He is Scientific Editor and co-author of first Polish academic handbook on Alzheimerʼs disease and ten another academic handbooks from old age psychiatry (Polish and internationals), member a lot of scientific associations eg. founder and president of Lower Silesian Association of Alzheimerʼs Families, first of its kind in Poland, President of the Scientific Council of Alzheimerʼs Disease Center in Scinawa, near Wroclaw, Former President and founder of Polish Psychogeriatric Association, Former Secretary (now member) of European Old Age Psychiatry and Former Member of Board of Directions of International Psychogeriatric Association.

Can We Currently Slow Down the Progression of Alzheimerʼs Disease?

Naji Tabet

Brighton and Sussex Medical School, United Kingdom

Currently there is no cure for Alzheimerʼs disease and available pharmacological treatment is at best symptomatic and does not work for everyone. Further, all randomised clinical trials testing disease modifying treatments have failed although many antiamyloid and anti-tau drugs are still in phase II and III phases clinical trials. This talk will first concentrate on available treatments and will assess whether memory enhancersʼ use is being currently optimised for patients. In recognition of the limitations of current treatment, the talk will then systematically assess non-pharmacological interventions in patients already diagnosed with Alzheimerʼs disease to assess whether there is any evidence of efficacy. The evidence presented will be obtained from systematic reviews as well as the speakers group own work in exercise, diet and bilingualism (as a measure of cognitive reserve). Non-pharmacological interventions discussed will include exercise, diet, social networks, bilingulaism and sleep.

It may be possible that by maximising currently available treatments and enhancing life style interventions for patients with mild to moderate Alzheimerʼs disease that we may be able to improve the health and the quality of life for patients and at least slow down some of the disturbing associated symptoms.

Naji Tabet is a Reader at Brighton and Sussex Medical School, United Kingdom and an Honorary Consultant in Old Age Psychiatry. His clinical and research interests and expertise are in the field of dementia. He and his team are investigating non-pharmacological interventions, lifestyles factors and co-morbid physical illnesses in relation to disease progression.Current research includes areas such as sleep, bilingualism, diet and exercise in dementia. Tabet has also been the Chief and Principal Investigator on nearly 30 Phase II-IV pharmacologically sponsored clinical studies assessing new treatment and diagnostic modalities in dementia disorders.

Multifaceted Properties of Human Serum Albuminas a Potential Therapeutic Approach to Treat Alzheimerʼs Disease

Beka Solomon

Tel Aviv University, Israel

Alzheimerʼs disease is neurodegenerative disorder involving many related and interdependent pathologies that manifests simultaneously.

No treatment is currently available; however, an agent addressing several key pathologies simultaneously has a better therapeutic potential. Human serum albumin (HSA) is a highly versatile protein, harboring multifunctional properties that are relevant to key pathologies. HSA decreased with aging and is associated with cognitive impairment in the elderly, further implicating its involvement in AD. HSA affect AD pathologies from several different aspects such as antioxidant activity, detoxification, anti-inflammatory properties, reduce BBB permeability and promote neuronal survival. All of these properties have significance in relation to AD pathology especially it interacts directly with amyloid beta peptide (Aβ), one of the hallmark pathologies in AD. HSA and Aβ interaction in vitro, show that HSA can reduce oligomeric Aβ and induced cellular stress in vitro due to direct binding to Aβ rather than other properties of HSA.

In vivo, we treat the mice with pumps infusing HSA intracerebroventricularly (ICV), in an AD 3xTg mice model. A significant effect on amyloid-β (Aβ) pathology was observed. Aβ1-42, soluble oligomers, and total plaque area were reduced as well as total and hyperphosphorylated tau. HSA treatment also reduced brain inflammation, affecting both astrocytes and microglia markers. Finally, evidence for blood-brain barrier and myelin integrity repair was observed. The work presented here shedding light over the mechanism of HSA and Aβ interaction and demonstrate that ICV administration of HSA is a potential therapeutic approach with multifaceted beneficial effects to treat AD

Professor Beka Solomon earned her Ph.D. in 1976 from the Weizmann Institute of Science, Rehovoth, Israel. She joined Tel-Aviv University in 1979 following post-doctoral studies and training periods at Harvard Medical School and Brigham and Womenʼs Hospital, Boston, USA. She is a member of the editorial board of Drugs of Today, Recent Patents on CNS Drug Discovery, of Neurodegenerative Diseases and Journal of Alzheimerʼs Disease. She was awarded the prestigious Zenith Award of the Alzheimer Association, and received the Dana Foundation Award for Neuroimmunology. In 2007 she was included in Scientific Americanʼs List of 50 of the Worldʼs Leading Innovators.

The Functional Ramifications of TREM2 Variants in Human Induced Pluripotent Stem Cell Derived Microglia-like Cells

Jennifer M. Pocock*, Pablo Garcia Reitboeck, Alexandra Phillips, Thomas M. Piers, Claudio Villegas Llerena, Anna Mallach, Amanda Heslegrave, Henrik Zetterberg, Harald Neumann, Stephen Neame, Henry Houlden and John Hard

University College London Institute of Neurology, United Kingdom

The dysfunction of microglia, the brainʼs immune cells, is linked to dementia. Heterozygous variants in the gene Triggering Receptor Expressed on Myeloid Cells (TREM2) are associated with late-onset Alzheimerʼs disease, whilst homozygous variants cause Nasu-Hakola disease (NHD), an early-onset dementia. Here, we generated induced pluripotent stem cell-derived microglialike cells (iPSC-MGLC) from patients with NHD caused by a homozygous T66M or W50C variant in the TREM2 gene, unaffected T66M heterozygous relatives and controls. Human iPSC-MGLC expressed microglial markers, and expressed and secreted TREM2. TREM2 expression and secretion were reduced in TREM2 variant iPSC-MGLC, which also exhibited impaired phagocytosis of apoptotic neuronal cells, but not other substrates. Cytokine secretion was unaffected. Taken together, these findings highlight the ramifications of TREM2 variants in robust human models of microglia.

Jennifer Pocock hold a degree in Applied Biology (1st class, specializing in Cell Biology, Biochemistry and Physiology) and a PhD in Neurophysiology. She had undertaken postdoctoral research at the University of Dundee, Scotland, UK and the University of California, USA. She is currently a Senior Lecturer in the Department of Neuroinflammation, University College London Institute of Neurology, London, UK. His research focus is to understand the role of inflammatory particularly microglia, the immune cell of the brain, in disease progression, especially in Alzheimerʼs Disease. His laboratory is currently using human fibroblast derived iPSCs expressing mutations in the TREM2 receptor, linked to Alzheimerʼs disease (R47H), Nasu Hakola disease (T66M, W50C) as well as CRISPR edited BV2 microglia for TREM2 KD and KO with which we are investigating signalling pathway deviations from control common variant cells.

Pathogenic Role of FcγRIIb in Amyloid and Tau Pathogenesis in Alzheimerʼs Disease

Yong-Keun Jung1*, Youngdae Gwon1, Tae-In Kam1,2, Seo-Hyun Kim1 and Dong-Gyu Jo2

1School of Biological Sciences, Seoul National University, Korea
2School of Pharmacy, Sungkyunkwan University, Korea

Amyloid-beta (Aβ) induces neuronal loss and cognitive deficits and is believed as a prominent cause of Alzheimerʼs disease (AD). However, cellular mechanism of the pathogenesis is not fully understood. Here we show that Fcgamma-receptor IIb (FcγRIIb) mediates Aβ neurotoxicity and neurodegeneration. We found that FcγRIIb is a receptor of Aβ1-42- oligomers and genetic depletion of FcγRIIb rescues the memory impairments in AD model mice. In addition, the FcγRIIb-SHIP2 axis is critical in Aβ1-42-induced tau pathology. Fcgr2b knockout or antagonistic FcγRIIb antibody inhibited Aβ1-42-induced tau hyperphosphorylation and rescued memory impairments in AD mouse models. As a action model, SHIP2 is recruited into phosphorylated FcγRIIb to affect PtdIns(3,4)P2 metabolism for tau phosphorylation. Further, targeting SHIP2 expression by lentiviral siRNA in 3xTg-AD mice or pharmacological inhibition of SHIP2 potently rescued tau hyperphosphorylation and memory impairments. Thus, we conclude that the FcγRIIb-SHIP2 axis links Aβ neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P2 metabolism, providing insight into therapeutic potential against AD. More, emerging evidences suggest that intraneuronal Aβ correlates with the onset of Alzheimerʼs disease (AD) and highly contributes to neurodegeneration. Our findings illustrate that FcγRIIb2 is essential for neuropathogenic function of Aβ in AD.

Yong-Keun Jung obtained his Ph.D from the Albert Einstein College of Medicine, NY, USA at 1993. From 1993-1996, he was a post-doctoral fellow in the department of cell biology, Harvard Medical School, USA. He then returned to Korea and is now a professor at Department of Biological Science, Seoul National University (SNU), Korea. He contributed to elucidation of the cell death machinery and our understanding of its association with human disease. In particular, the role of cell death and autophagy in the pathogenesis of human disease, including Alzheimerʼs disease, ischemia and cancer etc, is being investigated.

Neuroprotective Effect of Chia Seeds Extract on Aluminum Chloride Induced Alzheimerʼs Rat Model

Eman Abdelnaby

Cairo University, Egypt

Alzheimerʼs disease (AD) is the most common form of dementia, associated with irreversible neuropathological and neurobehavioral changes accompanied by memory and cognitive impairments. Despite the overwhelming evidence that links oxidative stress and AD, antioxidant therapies have limited success in clinical trials. The present study was aimed to evaluate the protective effect of Chia seeds extract on aluminum chloride (AlCl3) induced rat model. Oral administration of AlCl3 (200 mg/kg) for 60 days significantly elevated the levels of aluminum (Al), activity of acetylcholinesterase (AChE) and protein expressions of amyloid precursor protein (APP) compared to control group in hippocampus and cortex of rat brain. Chia seeds extract was administrated orally along with AlCl3 for 60 days (day after day protocol), significantly revert the Al concentration, AChE activity and Ab synthesis-related molecules in the studied brain regions. Our results showed that the behavioral impairments caused by aluminum were significantly attenuated by Chia seeds extract. As the spontaneous locomotor and exploratory activities in open field test were significantly reduced and the learning and memory impairments in Novel Object Recognition (NOR) test were enhanced. The histopathological studies in the hippocampus and cortex of rat brain also supported that Chia seeds extract markedly reduced the toxicity of AlCl3 and preserved the normal histoarchitecture pattern of the hippocampus and cortex. From these results, it is concluded that Chia seeds can reverse memory loss caused by aluminum intoxication through attenuating AChE activity and amyloidogenic pathway.

Eman H. Abdelnaby is an Ethologist who has graduated from Cairo University, Egypt. She has earned her Masterʼs in Animal Behavior. She is currently enrolled in her PhD in Alzheimerʼs Disease (AD), her study is about developing new herbal approaches (natural antioxidants) in AD Rat model. She was a professional fellow that visited several academic institutions as a scholar, including MBNI and ULAM-Michigan University, MSU- USA. Also joined an AD scientific project as an Erasmus+ student at Alexandru Ioan Cuza University, Romania. She has more than 7 years of research and teaching experience as an assistant lecturer and academic advisor. She is also a Certified Life Coach, a Certified Professional Trainer accredited from Missouri State University and a member of the “Board of International Trainers”, and currently acting as a Mentor at MENA-Michigan Initiative for Global Action through Entrepreneurship (M2GATE) program.

Copper Homeostasis in Relation to Cognitive Dysfunction in Neurodegenerative Disorders

Rosanna Squitti

IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Italy

Trace metal dyshomeostasis has been linked to cognitive deterioration and in particular a disturbance in the regulation of copper (Cu). Excess Cu not bound to ceruloplasmin (non-Cp Cu, also referred to as ‘free’ Cu), is thought to play a role in the development of Alzheimerʼs disease (AD). Non-Cp Cu is redox active and its toxicity results from its ability to accelerate oxidative stress via Fenton-like and Haber Weiss chemistry reactions.

The plasma component of non-Cp Cu is composed of Cu loosely bound to albumin, transcuprein, peptides and amino acids and it is exchanged among them. It makes up 5-10% of plasma Cu in normal condition. If the non-Cp Cu pool becomes expanded, this Cu becomes toxic, as exemplified by Wilsonʼs disease and reported in AD and other neurodegenerative diseases.

Non-Cp Cu may serve as a biomarker for cognitive impairment in AD. Elevated levels of non-Cp Cu in serum increase the probability of having AD by approximately three-fold. Subjects with mild cognitive impairment (MCI, a prodromal stage of AD) have elevated non-CpCu levels and a hazard rate of conversion to AD three times higher than those with normal non-CpCu values. These results suggest that abnormalities of Cu act at early stages of the disease. This concept is further supported by the finding that an increased frequency of variants in the ATP7B gene, which is a major regulator of non-Cp Cu levels, associates with the risk (odds ratio from 1.63 to 5.16) of having AD. Non-Cp Cu appears to be increased also in Parkinsonʼs disease and in corticobasal degeneration but not in frontotemporal lobar dementia.

Recent studies support the existence of a Cu subtype of AD, typified by increased levels of non-Cp Cu, exhibiting peculiar ATP7B gene, neurophysiological and neuroimaging patterns.

Rosanna Squitti, PhD, works in Italy with Fatebenefratelli Institutes, and she is visiting Scholar at the University of Miami (Fl, US). She is author of more than 100 peer reviewed publications and 2 patents. She contributed to the understanding of Alzheimerʼs disease (AD) by demonstrating the existence of a copper imbalance in AD, consisting in systemic excess copper not bound to ceruloplasmin (non-Cp Cu) and decreased protein-bound copper in the brain. She demonstrated that ATP7B gene, which is a major regulator of non-Cp Cu levels, associates with the AD risk, supporting the existence of a Cu subtype of AD.

Recombinant Human Hsp70 Exhibit a Significant Neuroprotective Effect in Two Mouse Models of Alzheimerʼs Disease

David Garbuz1*, G.Krasnov1, A.Morozov1, N.Bobkova2, Tatarnikova O2 and M.Evgenʼev1

1Engelhardt Institute of Molecular Biology, Russia
2Institute of Cell Biophysics, Russia

Molecular chaperone Hsp70 plays protective role in various neurodegenerative disorders including Alzheimerʼs disease (AD). Our data suggest that human recombinant Hsp70 effectively crosses the blood-brain barrier when administrated intranasally and exhibits dramatic neuroprotective effect in the bilateral olfactory bulbectomy (OBX mice) and transgenic 5XFAD mouse models of AD-like neurodegeneration. Chronic treatment by recombinant Hsp70 leads to a decrease of beta-amyloid level and restores the neuron morphology and density in the temporal cortex and hippocampal regions. In both mouse models of AD recombinant Hsp70 restored cognitive functions including learning and memory. Besides, Hsp70 treatment normalizes a number of biochemical indicators of the state of the nervous system in the aged animals, including lipofuscin and synaptophysin levels. Using deep sequencing, we identified multiple differentially expressed genes (DEGs) in the hippocampus of transgenic and non-transgenic mice of different age groups. Importantly, the pattern of DEGs strongly depends on the transgenicity and age of the experimental animals. Thus, upregulation of inflammatory and proteasomal genes is a feature of old transgenic 5XFAD mice. This analysis also demonstrated that recombinant Hsp70 administration strongly modulates the spectrum of DEGs in transgenic animals, reverting it to a pattern similar to that observed in non-transgenic mice of the same age. These changes include upregulation of genes responsible for amine transport, transmission of nerve impulses, synaptic transmission, dopamine metabolic processes and other pathways that are impaired in transgenic 5XFAD mice. Overall, our data indicate that chronical Hsp70 treatment may be an effective therapeutic against neurodegenerative diseases of the Alzheimerʼs type.

David G. Garbuz was born in 1978. He is Student of Moscow Veterinary Academy from 1995– 2000. He is the PhD Student of Engelhardt Institute of Molecular Biology Russian Academy of Sciences from 2000 – 2003. He did PhD in molecular biology at 2004. He is a researcher at Engelhardt Institute of Molecular Biology RAS from 2003 – 2008. He did Postdoctorate at USA, New-York, NYU Medical Centre from 2008 – 2009. He is the Assistant Professor at Moscow Veterinary Academy from 2008 – 2011. At present he is a Senior Research Scientist at Engelhardt Institute of Molecular Biology RAS from 2009. He received the degree of Doctor of Biological Sciences, the highest scientific degree in Russia at 2018.

Diagnosis of the Home Care for Persons with Alzheimer in Portugal: Current Situation and Perspectives

Eduardo Santos*, Rita Alberto and Carolina Neves

University of Coimbra, Portugal

The home care for patients with Alzheimerʼs disease is an increasing clinical and social practice in the field of dementia and ageing. The goal of this study is to make a diagnosis of the situation in Portugal. The results of an online survey about this subject are presented, showing that in Portugal there are no sufficient and specialized answers, in what concerns assisted active living methodologies performed by interdisciplinary teams. From this evidence it is discussed how to implement efficient practices in order to offer care options for patients and caregivers.

Eduardo Santos is Associated Professor of Counseling Psychology at the College of Psychology and Education, University of Coimbra, Portugal, and Adjunct Professor at the State University of New York, at Albany, USA. He is the Scientific Coordinator of the research, development and innovation unit Institute of Cognitive Psychology, Human and Social Development, University of Coimbra, articulating with national and international institutions within postgraduate research and training fields. His current interests focus on systemic-developmental processes along the life-span with emphasis in biotechnopsychosocial perspectives. He is author of a large number of books, scientific articles, and presentations at national and international levels.

Copper Homeostasis in Frontotemporal Lobar Degeneration

Rosanna Squitti

IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Italy

Trace metal dyshomeostasis has been linked to cognitive deterioration and in particular a disturbance in the regulation of copper (Cu). Excess Cu not bound to ceruloplasmin (non-Cp Cu, also referred to as ‘freeʼ Cu), is thought to play a role in the development of Alzheimerʼs disease (AD). Non-Cp Cu is redox active and its toxicity results from its ability to accelerate oxidative stress via Fenton-like and Haber Weiss chemistry reactions.

The plasma component of non-Cp Cu is composed of Cu loosely bound to albumin, transcuprein, peptides and amino acids and it is exchanged among them. It makes up 5-10% of plasma Cu in normal condition. If the non-Cp Cu pool becomes expanded, this Cu becomes toxic, as exemplified by Wilsonʼs disease and reported in AD and other neurodegenerative diseases.

Elevated levels of non-Cp Cu in serum increase the probability of having AD by approximately three-fold. Meta-analyses show copper dyshomeostasis in Alzheimerʼs disease. However, a study evaluating copper changes in other neurodegenerative forms of dementia has not yet been performed. In this study, we assessed copper, ceruloplasmin, copper not bound to ceruloplasmin and copper to ceruloplasmin ratio in 85 patients affected by Frontotemporal Lobar Degeneration (FTLD) and 55 healthy controls. Data were analysed through multivariate ANOVA models taking into account age and sex as covariates and the stratification for FTLD variants, after calculating power analysis to ensure the reliability of the conclusions drawn. The study revealed no difference between the groups.

Rosanna Squitti, PhD, works in Italy with Fatebenefratelli Institutes, and she is visiting Scholar at the University of Miami (Fl, US). She is author of more than 100 peer reviewed publications and 2 patents. She contributed to the understanding of Alzheimerʼs disease (AD) by demonstrating the existence of a copper imbalance in AD, consisting in systemic excess copper not bound to ceruloplasmin (non-Cp Cu) and decreased protein-bound copper in the brain. She demonstrated that ATP7B gene, which is a major regulator of non-Cp Cu levels, associates with the AD risk, supporting the existence of a Cu subtype of AD.

Cerebrospinal and Serum Alpha-synuclein Species as Potential Biomarkers for Parkinsonʼs Disease

Omar M. A. El-Agnaf*, Sultan A. Salem, Katerina E. Paleologou, Martin D. Curran, Mark J. Gibson, Jennifer A. Court, Michael G. Schlossmacher and David Allsop

Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar

Developing effective treatments for neurodegenerative diseases is one of the greatest medical challenges of the 21st century. Parkinsonʼs disease (PD) and dementia with Lewy bodies (DLB) are very common neurological disorders of the elderly. Although many of these clinical entities have been recognized for more than a hundred years, it is only during the past fifteen years that the molecular events that precipitate the diseases have begun to be understood. Mutations in the alpha-synuclein gene cause early-onset PD, often associated with dementia. Neuropathologically these diseases are characterized by the presence of Lewy bodies, intraneuronal inclusions mostly composed of alpha-synuclein protein fibrils. Despite the progress that has been made in understanding the underlying disease mechanisms of PD and DLB, there remains an urgent need to develop methods for use in diagnosis. The development of reliable surrogate markers for the presence and abundance of alpha-synuclein lesions (Lewy bodies) in the brain would naturally facilitate a more streamlined work-up during the early care of PD and DLB patients, and importantly, allow for the biologically guided evaluation of future drug trials aimed at neuroprotection in the synucleinopathies. In this seminar, I will present the progress which has been made so far by our group to explore the use of CSF α-synuclein and its modified forms as biomarkers for PD and related disorders.

Omar El-Agnaf is acting Executive Director at Qatar Biomedical Research Institute (QBRI) and Director of Neurological Disorders Research Center at QBRI. His primary research concerns neurodegenerative disease. Since he moved to the region, he has assembled an excellent research team and has been successful in attracting an array of scientific funding from prestigious international funding agencies. Dr. El-Agnaf is frequently invited as a speaker at international scientific and clinical meetings and is currently a member of the editorial board of several international journals. His track record of basic and translational research productivity is characterized by publications in high-ranking scientific journals. He is considered a pioneer in the field of Parkinsonʼs disease and related neurodegenerative diseases. Several inventions have emerged from his research and provided new insights into the molecular pathogenesis of neurodegenerative diseases and have offered new opportunities for the development of novel diagnostic and therapeutic tools for Parkinsonʼs disease and related disorders. His research has also been translated into clinical studies to evaluate novel markers as diagnostic tools for neurodegenerative diseases. He has been granted 8 patents and 6 under consideration, and published more than 120 refereed articles, with 52 h-index and total citations >8,600.

Dyskinesias-Reduced-Self-Awareness in Patients with Parkinsonʼs Disease. A Neurocognitive Approach

Sara Palermo1*, Rosalba Morese2, Maria Consuelo Valentini3, Mario Stanziano3, Maurizio Zibetti4, Leonardo Lopiano4 and Martina Amanzio1

1Department of Psychology - University of Turin, Italy
2Faculty of Communication Science - Università della Svizzera Italiana, Switzerland
3Neuroradiology Unit - AOU “Città della Salute e della Scienza di Torino”, Italy
4Department of Neuroscience - University of Turin, Italy

Parkinsonʼs disease (PD) patients may be partially or even completely unaware of the presence of involuntary movements in terms of dyskinesias-reduced-self-awareness (DRSA). As the association with executive dysfunction is a matter of debate and we hypothesize it plays an important role in DRSA, we previously analyzed the role of dopaminergic treatment on the medial-prefrontal-ventral-striatal circuitry using a neurocognitive approach. Indeed, we have given special attention to metacognitive abilities related to action-monitoring and other factors, such as “Theory of Mind”, that represent a novel explanation of the phenomenon.

Importantly, response-inhibition dysfunction is often observed in PD. Besides being involved in response-inhibition, the anterior cingulate cortex (ACC) is part of a functional system based on self-awareness and engaged across cognitive, affective and behavioral contexts. In a new study, we used an event-related fMRI to verify the association between response-inhibition disabilities and DRSA. The presence of DRSA was assessed using the DyskinesiasSubtracted-Index (DS-I). Cingulate functionality was evaluated with fMRI, while patients performed an ACC-sensitive GO-NoGO task. Association between blood oxygenation level dependent response over the whole-brain during the response-inhibition task and DS-I scores was investigated.

The presence of DRSA result associated with a reduced functional recruitment in the bilateral ACC, bilateral anterior insular cortex and right dorsolateral prefrontal cortex (p <0.05). Moreover, DS-I scores significantly correlated with percent errors on the NoGO condition (r = .491, p = .009).

These findings add evidence to the relevant role of executive dysfunctions in DRSA pathogenesis, with a key role played by ACC.

Sara Palermo is MSc in Clinical Psychology and PhD in Experimental Neuroscience. She is Postdoc Research Fellow at the University of Turin, while she is ordinary member of the Italian Society of Neuropsychology and of the Italian Association of Psychogeriatrics. Importantly, she is a research member of the European Innovation Partnership on Active and Healthy Aging, for which she is involved in the Action Group A3 “Functional decline and frailty”. Sara Palermo is part of the Editorial Panel of “EC Psychology and Psychiatry” (ECPP), an internationally peer reviewed journal aimed to publish topics related to psychology and medicine.

Tau Protein in Oral Mucosa and Cognitive State: A Cross-Sectional Study

Robert A. Norman4*, Luis Fernando Arredondo1, Saray Aranda-Romo2, Ildefonso Rodríguez-Leyva3, Erika Chi-Ahumada1, Sami K. Saikaly4, Diana P. Portales-Pérez5,6, Roberto González-Amaro6, Mariana Salgado-Bustamante1, Lourdes Enriquez-Macias1, William Eng4 and Maria E. Jimenez-Capdeville1

1Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Mexico
2Clínica de Diagnóstico, Facultad de Estomatología, Universidad Autonóma de San Luis Potosi, Mexico
3Departamento de Neurología, Hospital “Ignacio Morones Prieto”, Mexico
4University of Central Florida College of Medicine, USA
5Laboratorio de InmunologíaBiologiaCelulary Molecular, Facultad de CienciasQuímicas, Universidad Autónoma de San Luis Potosi, Mexico
6Centro de InvestigaciónenCiencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, Mexico

Neurodegenerative diseases are characterized by the presence of abnormal aggregates of proteins in brain tissue. Among them, the presence of aggregates of phosphorylated Tau protein (p-Tau) is the hallmark of Alzheimerʼs disease (AD) and other major neuro-degenerative disorders such as corticobasal degeneration and frontotemporal dementia among others. Although Tau protein has previously been assumed to be exclusive to the central nervous system, it is also found in peripheral tissues. The purpose of this study was to determine whether there is a differential Tau expression in oral mucosa cells according to cognitive impairment. Eighty-one subjects were enrolled in the study and classified per Mini-Mental State Examination test score into control, mild cognitive impairment (MCI), and severe cognitive impairment (SCI) groups. Immunocytochemistry and immunofluorescence revealed the presence of Tau and four p-Tau forms in the cytoplasm and nucleus of oral mucosa cells. More positivity was present in subjects with cognitive impairment than in control subjects, both in the nucleus and cytoplasm, in a speckle pattern. The mRNA expression of Tau by quantitative real-time polymerase chain reaction was higher in SCI as compared with the control group (P<0.01). A significantly higher percentage of immunopositive cells in the SCI group was found via flow cytometry in comparison to controls and the MCI group (P <0.01). These findings demonstrate the higher presence of p-Tau and Tau transcript in the oral mucosa of cognitively impaired subjects when compared with healthy subjects. The feasibility of p-Tau quantification by flow cytometry supports the prospective analysis of oral mucosa as a support tool for screening of proteinopathies in cognitively impaired patients.

Keywords: tau protein, dementia, neurodegenerative diseases, alzheimer disease, oral mucosa cells