8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 1 Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework** Consortium leader PETER PAZMANY CATHOLIC UNIVERSITY Consortium members SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund *** **Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben ***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg. PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS UNIVERSITY sote_logo.jpg dk_fejlec.gif INFOBLOKK 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 2 Peter Pazmany Catholic University Faculty of Information Technology BASICS OF NEUROBIOLOGY NEURODEGENERATION www.itk.ppke.hu Neurobiológia alapjai (Neurodegneráció) ZSOLT LIPOSITS Basics of Neurobiology: Neurodegeneration 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 3 www.itk.ppke.hu VULNERABILITY OF THE NERVOUS SYSTEM AFTER COMPLETION OF THE DEVELOPMENT OF THE BRAIN, THE BASIC NEURONAL NETWORKS SERVING BRAIN FUNCTIONS GET ESTABLISHED THE CONNECTIONS FORMED AMONG NEURONAL ASSEMBLIES MAINTAIN A REMARKABLE FUNCTION-DEPENDENT PLASTICITY AND THE ABILITY OF STRUCTURAL AND FUNCTIONAL REMODELING IN THE MATURE BRAIN, NEURONS DO NOT DIVIDE ANYMORE, THEREFORE, THE ORIGINAL NEURON SETUP SERVES FOR LIFE SPAN FROM STEM CELLS, HOWEVER, A LIMITED SUPPLY OF CERTAIN NEURON TYPES OCCURS IN THE CNS THE COMPLEX ARCHITECTURE, THE CHARACTERISTIC NETWORKING, THE HIGH METABOLIC NEEDS AND THE LACK OF A SUBSTANTIAL REGENERATIVE SUPPLY OF NEURONS MAKE THE BRAIN EXTREMELY VULNERABLE Basics of Neurobiology: Neurodegeneration 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 4 www.itk.ppke.hu CAUSES OF NEURAL TISSUE DAMAGE GENETIC MUTATIONS: TRINUCLEOTIDE (CAG) REPEAT EXPANSION DISORDERS (HUNTINGTON’S DISEASE) TRAUMATIC BRAIN INJURY: HEMORRHAGIC CONTUSIONS TUMOR: MALIGNANT AND BENIGNANT CELL PROLIFERATIONS INFECTION: INFLAMMATION CAUSED BY BACTERIA AND VIRUSES (ENCEPHALITIS) OXIDATIVE STRESS: SUPEROXIDE RADICAL, HYDROGEN PEROXIDE CHEMICAL DAMAGE: ALCOHOL, DRUG ABUSE, ORGANIC SOLVENTS ISCHEMIA: RESTRICTION IN BLOOD SUPPLY (ARTERIOSCLEROSIS) HYPOXIA: SHORTAGE IN OXYGEN SUPPLY AGING: STRUCTURAL AND NEUROCHEMICAL PROPERTIES OF NEURONS CHANGE Basics of Neurobiology: Neurodegeneration 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 5 www.itk.ppke.hu NECROTIC AND APOPTOTIC DEGENERATION OF NEURONS HYPOXIA GROWTH FACTOR SHORTAGE INTACT NEURON NECROTIC NEURON APOPTOTIC NEURON Basics of Neurobiology: Neurodegeneration 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 6 www.itk.ppke.hu APOPTOTIC DEATH OF NEURONS NEURONS UNDERGOING APOPTOSIS SHOW A CHARACTERISTIC MORPHOLOGY: CELL SHRINKAGE AND ROUNDING DUE TO THE BREAKDOWN OF THE CYTOSKELETON BY CASPASES THE CYTOPLASM APPEARS DENSE, THE ORGANELLES APPEAR TIGHTLY PACKED CHROMATIN UNDERGOES CONDENSATION INTO COMPACT PATCHES AGAINST THE NUCLEAR ENVELOPE. PYKNOSIS, A HALLMARK OF APOPTOSIS THE NUCLEAR ENVELOPE BECOMES DISCONTINUOUS AND THE DNA FRAGMENTED THE CELL MEMBRANE SHOWS IRREGULAR BUDS KNOWN AS BLEBS THE CELL BREAKS APART INTO SEVERAL VESICLES CALLED APOPTOTIC BODIES WHICH BECOME PHAGOCYTOSED PYCNOTIC NUCLEUS IN AN APOPTOTIC CELL Basics of Neurobiology: Neurodegeneration 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 7 www.itk.ppke.hu NECROSIS OF NEURONS NEURONS UNDERGOING NECROSIS SHOW SPECIFIC MORPHOLOGICAL SIGNS: INCREASED ACIDOPHILIC STAINING IN LM PREPARATIONS INCREASED AND INTENSE ARGYROPHILIA MAJOR DARKENING AND SHRINKAGE OF THE NUCLEUS AND CYTOPLASM PLASMA MEMBRANE AND THE NUCLEAR MEMBRANE BECOME IRREGULAR THE CYTOPLASM GENERALLY CONTAINS MANY LARGE VACUOLES SWOLLEN MITOCHONDRIA WITH DISRUPTED CRISTAE PLENTY AUTOPHAGIC VACUOLES INCREASED ASTROCYTE AND MICROGLIA ACTIVITY IN THE VICINITY THE NEURONS FALL APART AND GET PHAGOCYTOSED D DEGENERATING, NECROTIC NEURON (D) SHOWS HIGH ELECTRON DENSITY IN THE VICINITY OF NORMAL NEURONS (STARS) Basics of Neurobiology: Neurodegeneration 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 8 www.itk.ppke.hu WALLERIAN DEGENERATION OF NEURONS AFTER AXON TRANSECTION CUT MAIN FEATURES: EXCENTRIC NUCLEUS ENLARGED PERIKARYON CHROMATOLYSIS DISTAL AXON STUMP DEATH BREAKDOWN OF MYELIN MICROGLIA INFILTRATION OCCURS IN CNS AND PNS Basics of Neurobiology: Neurodegeneration 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 9 www.itk.ppke.hu DEGENERATING GRANULE CELLS IN THE HIPPOCAMPUS CORTICOSTERONE DEPRIVATION EVOKES GRANULE CELL DEGENERATION IN THE HIPPOCAMPUS DARK BODIES OF DEGENERATING CELLS ARE VISIBLE (D) HYPERTROPHIC ASTROCYTE PROCESSES ARE NUMEROUS IN THE FIELD (A) MICROGLIA (MG) IS IN THE VICINITY OF DETERIORATING NEURONS WITH ENGULFED NECROTIC PARTS OF THE CELLS (I) Basics of Neurobiology: Neurodegeneration 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 10 www.itk.ppke.hu EXPERIMENTAL USE OF AXOTOMY FOR DETECTION OF NEURONAL PATHS 1. LESION PLACED IN FRONT OF THE PARAVENTRICULAR NUCLEUS (PVN) HAS NO EFFECT ON CRH AXON IMMUNOREACTIVITY IN THE MEDIAN EMINENCE (ME) 2. PARTIAL DESTRUCTION OF THE PVN RESULTS IN THE DECREASE OF CRHAXON IMMUNOREACTIVITY IN THE MEDIAN EMINENCE 3. TOTAL ABOLISHMENT OF THE PVN EMPTIES THE CRH CONTENT OF THE MEDIAN EMINENCE DUE TO DEGENERATION OF CRH AXONS 1. 3. 2. Basics of Neurobiology: Neurodegeneration 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 11 www.itk.ppke.hu CHEMICAL LESIONINGOF THE BRAIN 1. ADMINISTRATION OF THE EXCITATORY KAINIC ACID TO MICE AT A 40 mg/kg DOSE EVOKES c-FOS ACTIVATION (A) IN NEURONS OF THE CA3 SECTOR OF THE HIPPOCAMPUS 2. USING THE FLUORO-JADE STAINING FOR VISUALIZATION OF DEGENERATING PROFILES REVEALS AN INTENSE CELL DEATH OF PYRAMIDAL NEURONS IN THE CA3 REGION OF THE HIPPOCAMPUS 3. THE DEGENERATION IS DUE TO THE KAINIC ACID EVOKED EPILEPTIC SEIZURESTHAT BADLY DAMAGE HIPPOCAMPAL PYRAMIDAL CELLS A B Basics of Neurobiology: Neurodegeneration 8/5/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 12 www.itk.ppke.hu NEUROPATHOLOGY OF ALZHEIMER DISEASE ALZHEIMER DISEASE IS A SEVERE ILLNESS CHARACTERIZED BY NEURONAL DEGENERATION AND GRADUAL DECLINE OF COGNITIVE FUNCTIONS. IT MAYLEAD TO DEMENTIA SEVERAL CAUSES HAVE BEEN IMPLICATED IN THE PATHOGENESIS OF THE DISEASE: ACETYLCHOLINE, BETA-AMYLOD, TAU AND PRION HYPOTHESES THE FORMATION OF AMYLOD PLAQUES IN THE NERVOUS TISSUE (A) AND THE PRESENCE OF NEUROFIBRILLARY TANGLES (B) IN DEGENERATING NEURONSARE CHARACTERISTIC NEUROPATHOLOGICAL FEATURES A B