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Zur Bedeutung der Apolipoproteinexpression für die Entwicklung einer senilen Demenz vom Alzheimer-TypGlöckner, Frauke 01 March 2006 (has links)
Der bedeutendste Risikofaktor für die Demenz vom Azheimer Typ (DAT) ist, neben dem Alter, der Besitz des e4-Allels des Lipidtransportmoleküls Apolipoprotein E (APOE, Gen; ApoE, Protein). Neben funktionellen Unterschieden der Isoformen könnte auch die quantitative Verfügbarkeit des Proteins bei der Pathogenese der DAT eine Rolle spielen. Da ApoE als Lipidtransporter insbesondere bei plastischen Umbauprozessen in Gehirn wichtig sein könnte, wurde der Proteingehalt in Bezug auf die Schwere der DAT-assoziierten Veränderungen entsprechend der neuropathologischen Stadieneinteilung nach Braak untersucht. Neben ApoE wurde auch Apolipoprotein D (ApoD) in der Pathogenese der DAT diskutiert. Um herauszufinden, ob es hier eine Beziehung zur Schwere der neuropathologischen Veränderungen und/oder dem APOE-Polymorphismus gibt, wurde auch der ApoD-Gehalt untersucht. Bestimmt wurde der Apolipoproteingehalt in 104 nach Alter, Geschlecht, Braak-Stadium und APOE-Genotyp abgeglichenen Hippokampusproben, da diese Hirnregion im Verlauf einer Demenz früh und nachhaltig betroffen ist. Die Daten zeigen einen Anstieg von ApoE in den frühen Stadien der Erkrankung, in denen neuroplastische Reparationsvorgänge nachweisbar sind, und eine kontinuierliche Zunahme des ApoD-Gehalts mit der Schwere der neurofibrillären Veränderungen in den APOE e3/3-Proben. In den Proben, die das Risikoallel APOE e4 trugen, waren keine statistisch signifikanten Veränderungen nachweisbar. / The most important risk factor for Alzheimer´s disease (AD), besides age, is the inheritance of the e4-allele of the lipid transporting apolipoprotein E (APOE, gen; apoE, protein). Apart from functional differences of the apoE isoforms, the quantitative availability of the protein might be important in AD pathogenesis. As a lipidtransporter, apoE should be relevant especially during plastic response of neuronal structures. Hence, apoE levels were investigated in correlation to the severity of pathological changes as staged according to the neuropathological Braak classification of AD. Besides apoE, apolipoprotein D (apoD) is discussed in AD pathogenesis. To clarify whether there is a correlation to AD related neuropathological changes, apoD levels were also determined. The apolipoproteins were determined in 104 age-, gender-, Braak stage- and APOE genotype-matched samples of hippocampal protein extracts because this brain region is early and enduring affected by the disease. The data show an increase in apoE in the early stages of the disease where plastic remodelling occurs and a continuous increase in apoD with the severity of neurofibrillary changes in the APOE e3/3-group only. No statistically relevant changes were observed in samples carrying the AD-risk allele e4.
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Funktionelle Charakterisierung von BACE, einer für die Alzheimer Krankheit relevanten ProteaseCapell, Anja 10 August 2005 (has links)
Die Alzheimer Krankheit ist die häufigste Altersdemenz. Ein spezifisches pathologisches Merkmal der Alzheimer Krankheit ist die Amyloid-Ablagerung im Gehirn. Die Hauptkomponente der so genannten Amyloid-Plaques ist das Amyloid beta-Peptid (A-beta). A-beta entsteht durch sequenzielle proteolytische Spaltung aus einem membrangebundenen Vorläuferprotein, dem beta-APP (betaamyloid precursor protein). Die kürzlich identifizierte beta-Sekretase (BACE, beta-site APPcleaving enzyme) generiert den Schnitt am N-Terminus von A-beta. Es entsteht ein C-terminales, membrangebundenes beta-APP-Fragment, das beta-APP-CTF. Beta-APP-CTF ist das direkte Substrat für die gamma-Sekretase, die innerhalb der Membrandomäne schneidet, wodurch A-beta freigesetzt wird. In der vorliegenden Arbeit kann erstmalig gezeigt werden, dass BACE auf dem sekretorischen Transportweg aus dem Endoplasmatischen Retikulum (ER), über den Golgi-Apparat zur Zelloberfläche transportiert wird. Auf dem Transport wird BACE durch N-Glycosylierung und Propeptidabspaltung posttranslational modifiziert. BACE wird im ER N-glycosyliert und die mannosereichen Zucker werden auf dem Transport durch den Golgi-Apparat in Endoglycosidase H resistente Zucker des komplexen Typs modifiziert. Die Propeptidabspaltung, durch Furin oder furinähnliche Propeptidkonvertasen, findet unmittelbar vor dem Aufbau der komplexen Zucker statt. Ferner konnte gezeigt werden, dass der Transport von BACE die A-beta-Entstehung limitieren kann. In polarisierten Madin-Darby canine kidney (MDCK) Zellen wird BACE überwiegend zur apikalen Plasmamembran transportiert und damit entgegengesetzt zu seinem Substrat beta-APP. Der gegensätzliche Transport von BACE und beta-APP begrenzt die A-beta Entstehung. Wird der apikale Transport von beta-APP durch Deletion seines basolateralen Sortierungssignals erhöht, entsteht vermehrt A-beta. Der differenzielle Transport von BACE und beta-APP könnte ein Hinweis darauf sein, dass beta-APP nicht das physiologische Substrat von BACE ist. / Alzheimer`s disease is the most common cause of progressive cognitive decline in the aged population. Pathologically Alzheimer`s disease is characterized by the invariant accumulation of senile plaques. Senile plaques are predominantly composed of the amyloid beta-peptide (A-beta), which is derived from the membrane bound beta-amyloid precursor protein (beta-APP) by sequential proteolytic cleavage. The recently identified beta-secretase (BACE) is responsible for the cleavage at the N-terminus of the A-beta domain. This cleavage generates membrane-bound beta-APP-Cterminal fragments (beta-APP-CTF) which are the immediate precursor for gamma-secretase cleavage and therefore for liberation of A-beta. The present work shows that BACE moves along the secretory pathway, while it undergoes post-translational modifications, which can be monitored by a significant increase in the molecular mass and cleavage of its pro-peptide. BACE becomes N-glycosylated within the ER and the increase in molecular mass is caused by complex N-glycosylation. The mature form of BACE is resistant to endoglycosidase H treatment; this indicates that BACE traffics through the Golgi. Furthermore the mature form of BACE does not contain the pro-peptide anymore. Pro-BACE is predominantly located within the endoplasmic reticulum. Pro-peptide cleavage occurs immediately before full maturation by furin or a furin-like proprotein convertase. Moreover traffic of BACE can limit A-beta generation. In the well established model system of polarized Madin-Darby canine kidney (MDCK) cells, the majority of BACE is sorted to the apical domain. Interestingly it has been shown previously that the substrate of BACE, beta-APP is transported to the basolateral surface of MCDK cells. Therefore, substantial amounts of BACE are targeted away from beta-APP to a non-amyloidogenic compartment, a cellular mechanism that limits A-beta generation. Upon deletion of the basolateral sorting signal of beta-APP, apically missorted beta-APP is processed by BACE. The differential targeting of BACE and its substrate beta-APP suggest that beta-APP might not be the major physiological substrate of BACE.
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Telemetrische Erfassung von Verhaltensstörungen bei schwerer DemenzRapp, Michael Armin 12 July 2006 (has links)
Verhaltensstörungen bei Demenz sind von zentraler klinischer Bedeutung. Zur Beurteilung solcher Phänomene liegen eine Anzahl standardisierter Beobachtungsbögen vor. Problematisch sind diese Skalen im Hinblick auf ihre Reliabilität bei der Anwendung durch Angehörige und Pflegende. Wir schlagen daher die aktometrische Darstellung von motorischer Aktivität, wie sie etwa aus der Schlafforschung bekannt ist, vor. In dieser Dissertation wurde zunächst die Reliabilität und konkurrente Validität der Messung von motorischer Unruhe bei Demenz mittels eines aktometrischen Gerätes untersucht. Die Ergebnisse zeigen, dass die aktometrische Messung von Verhaltensstörungen eine valide und reliable Methode auch bei schwerer Demenz darstellt. Im zweiten Teils dieser Arbeit wurde unter quasiexperimenteller Kontrolle von Modulatoren der circadianen Rhythmizität Unterschiede der circadianen Rhythmik zwischen vaskulärer Demenz und Demenz vom Alzheimer-Typ untersucht. Dabei konnte gezeigt werden, dass es bei Patienten mit Demenz vom Alzheimer-Typ und bei Patienten mit vaskulärer Demenz in Abhängigkeit von der motorischen AktivitŠt zu einer charakteristischen Phasenverschiebung der circadianen Rhythmik kommt. Dieser Zusammenhang ist jedoch bei Alzheimer-Demenz, bei der von einer neurobiologischen Störung des suprachiasmatischen Nukleus ausgegangen werden kann, stärker ausgeprägt. Dieses Befundmuster unterstützt theoretische Modelle der circadianen Rhythmik und ihrer Störung bei Demenz und legt nahe, dass der suprachiasmatischen Nukleus bei Demenz vom Alzheimer-Typ eine zentrale Rolle bei der circadianen Regulation des Verhaltens einnimmt. / Behavioural signs and symptoms in dementia are of central clinical significance. There are a number of standardised rating scales available for the assessment of motor phenomena in dementia. However, there is no objective method of assessing these symptoms. In addition, the reliability of these scales, especially when used by caregivers from within families, has been questioned. In order to overcome this flaw, we propose the use of an actometric device for assessing behaviour motor symptoms in dementia. In the first part of this dissertation we assessed the reliability and the concurrent validity of an actometric device against two behavioural scales. Results show satisfactory validity and good reliability of this method. In the second part of this dissertation, we reanalysed data from our validation study, investigating whether the pattern of circadian rhythm disturbances is different in patients suffering from Alzheimer disease and patients suffering from vascular dementia, controlling experimentally for the severity of behaviour disturbances. With regards to circadian motor activity, we found increased nocturnal activity and fragmentation of diurnal rhythm in both groups. In patients showing an equal severity of behaviour disturbances, the phase-delay of the rest-activity rhythm was delayed in patients with Alzheimer disease as compared to patients with vascular dementia. These findings suggest that, in Alzheimer disease, structural changes in the SCN might induce disturbance in the circadian pacemaker, leading to a phase shift in the circadian rhythm. The differential pattern of rhythm disturbance found in this study could be indicative of different processes involved in sleep disorders in the dementias.
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Indicadores nutricionais em pacientes com doen?a de alzheimer: rela??es com fatores cl?nicos / Nutritional Indicators in Patients with Alzheimer's disease: Clinical factors relationshipSantos, Tamires Barbosa Nascimento dos 02 February 2017 (has links)
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Previous issue date: 2017-02-02 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / The increase of the population's average age, there was a prevalence increment on the chronic nerological disorders, degenerative such as the Alzheimer's Disease (AD). The deepening on the knowledge of the processes of lifestyle, regarding the nutritional state and its relations with the cognition are important for the guidance and conducting of the elderly people. This study aimed to analyze the nutritional status of elderly patients with AD and its relationship with the clinical aspects, neurocognitive, behavioral and lifestyle. 43 elderlies from the Clinical Neurology Ambulatory of the Celso Pierro Hospital and Maternity (PUCCampinas) were evaluated with the diagnosis of light, moderate and severe AD, according to the Clinical Dementia Rating (CDR) and 51 controls matched by age, gender, schooling and socioeconomic level, whith no history of cognitive decline. The procedures used were: clinical evaluation, mental State mini-exam, simple drawing memory, verbal fluency, clock drawing, functional ability, neuropsychiatric inventory (NPI), CDR, socioeconomic evaluation, physical and social activity (International Questionnaire of Physical Activity - IQPA short version), Mini Nutritional Assessment (MNA), Body mass Index (BMI), Waist circumference (WC), Arm Circumference (AC), Calf Circumference (CC), Triciptal Cutaneous Fold (TCF), Subscapular cutaneous fold (SCF), Muscular Arm circumference (MAC), Corrected Arm Muscle Area (CAMA), Thumb Adductor Muscle (TAM), Palmar Holding Force (PHF) and Bioelectric Impedance. Comparison were made between Alzheimer's Disease Group (ADG) and Control Group (CG) with sociodemographic aspects, lifestyle, cognitive, MNA, Nutritional indicators and nutritional indicators by gender Comparisons were made between CG and AD stages according to the CDR with nutritional variables, It were also performed correlations between PHF with anthropometric variables on the ADG and CG and between cognitive and anthropometric variables on the ADG. With suitable statistical tests the situation and level of significance of 5% in all cases. It was noticed that the ADG develops less social activity and has a smaller relationship network, less physically active, and has poor performance in Daily life activities, mostly in instrumental activities. GDA showed malnutrition with a decrease in total food intake and higher daily intake of some foods on the MNA. Among genders, woman showed diferences in most anthropometric measurements with lower values in the ADG. In the comparison between CG and fazes of ADG there were differences in some measures with lower values in the severe ADG, and higher in the CG. In the comparison between CG and ADG, CG versus light and moderate ADG versus severe ADG there was a difference for some anthropometric measurements. There were no differences between Light and Moderate stages. The Lean Mass (LM) composition measurements were lower in the ADG. No difference was seen on the WC and reactance comparison. There were correlations between PHF and anthropometric variables in the ADG but not between nutritional variables with socioeconomic aspects, behavioral, NPI, social and physical activities. The findings suggests a significant association between social and leisure activities during the eld and a lower dementia risk. In the MNA the lowest score indicates greater deterioration of mental state. As per the feeding, it was noticed that, possibly, ADG feeds with lower amount and higher quality, suggesting a better selection of food by the caregiver. The authors reports a significant difference between BMI in AD phases, with reduction in BMI at the severe stage compared to light and moderate. In the study, there was a greater presence of elderly individuals at malnutrition risk in the AD group when compared to the CG, suggesting that the malnutrition is a factor of risk to the dementia progression. The nutritionals variables were progressively more committed with the advancement of cognitive deficits, since there was a LM reduction trend with the AD progression, more evident in the transition from moderate to severe. / Com o aumento da idade m?dia da popula??o houve incremento de preval?ncia de afec??es neurol?gicas cr?nicas, degenerativas, como a Doen?a de Alzheimer (DA). O aprofundamento do conhecimento dos processos do estilo de vida no que se refere ao estado nutricional e de suas rela??es com a cogni??o s?o de import?ncia para orienta??o e conduta desses idosos. O objetivo desse trabalho foi analisar o estado nutricional de idosos com DA e sua rela??o com aspectos cl?nicos, neurocognitivos, comportamentais e de estilo de vida. Foram avaliados 43 idosos procedentes do ambulat?rio de Neurologia Cl?nica do Hospital e Maternidade Celso Pierro (PUC-Campinas) com diagn?stico de DA leve, moderado e grave, segundo o Clinical Dementia Rating (CDR) e 51 controles pareados por idade, g?nero, escolaridade e n?vel socioecon?mico, sem hist?ria de decl?nio cognitivo. Os procedimentos foram avalia??o cl?nica, Mini-Exame do estado mental, mem?ria do desenho simples, Flu?ncia Verbal, desenho do rel?gio, capacidade funcional, Invent?rio Neuropsiqui?trico (INP), CDR, avalia??o socioecon?mica, atividade f?sica (Question?rio Internacional de Atividade F?sica ? IPAQ vers?o curta) e sociais, Mini Avalia??o Nutricional (MAN), ?ndice de Massa Corp?rea (IMC), Circunfer?ncia da Cintura (CC), Circunfer?ncia do Bra?o (CB), Circunfer?ncia da Panturrilha (CP), Dobra Cut?nea Tricipital (DCT), Dobra Cut?nea Subescapular (DCSE), Circunfer?ncia Muscular do Bra?o (CMB), ?rea Muscular do Bra?o corrigida (AMBc), M?sculo Adutor do Polegar (MAP), For?a de Preens?o Palmar (FPP) e Imped?ncia Bioel?trica. Foi realizada a compara??o entre Grupo Doen?a de Alzheimer (GDA) e Grupo Controle (GC) com aspectos sociodemogr?ficos, estilo de vida, cognitivos, comportamentais, MAN, indicadores nutricionais e indicadores nutricionais por g?nero. Foram feitas compara??es entre GC e est?gios da DA de acordo com CDR com as vari?veis nutricionais, tamb?m foram realizadas correla??es entre FPP com vari?veis antropom?tricas no GDA e GC e entre vari?veis cognitivas e antropom?tricas no GDA. Com testes estat?sticos adequados a situa??o e n?vel de signific?ncia de 5% em todos os casos. Foi observado que o GDA desenvolve menos atividade social e tem rede de relacionamento menor, ? fisicamente menos ativo e tem desempenho inferior nas Atividades de Vida Di?ria, principalmente nas atividades instrumentais. O GDA apresentou desnutri??o com diminui??o da ingest?o alimentar total e maior ingest?o di?ria de alguns alimentos, na MAN. Entre os g?neros, as mulheres apresentaram diferen?a em mais medidas antropom?tricas, com valores menores no GDA. Na compara??o entre GC e fases do GDA, houve diferen?a em algumas medidas com valores menores no GDA grave e maior no GC. Na compara??o entre GC e GDA, GC versus GDA leve e moderado e GDA leve e moderado versus GDA grave houve diferen?a para algumas medidas antropom?tricas. N?o houve diferen?a entre os est?gios leve e moderado. As medidas de composi??o de Massa Magra (MM) foram menores no GDA. CC e Reat?ncia n?o apresentaram diferen?a em nenhuma compara??o. Houve correla??es entre FPP e vari?veis antropom?tricas nos GDA e n?o houve entre vari?veis nutricionais com aspectos socioecon?micos, comportamentais, INP, atividades sociais e f?sicas. Os achados da literatura sugerem uma associa??o significativa entre atividades sociais e de lazer durante a velhice e o menor risco de dem?ncia. Na MAN a menor pontua??o indica maior deteriora??o do estado mental. Quanto a alimenta??o, foi observado que possivelmente o GDA se alimenta com menor quantidade e maior qualidade, sugerindo uma melhor sele??o dos alimentos pelo cuidador. Os autores relatam diferen?a significativa entre IMC nas fases da DA, com redu??o no IMC no est?gio grave comparado ao leve e moderado. No estudo houve maior presen?a de idosos em risco de desnutri??o no grupo com DA quando comparados ao GC, sugerindo que a desnutri??o ? um fator de risco para a progress?o da dem?ncia. As vari?veis nutricionais foram progressivamente mais comprometidas com o avan?ar dos d?ficits cognitivos, pois houve uma tend?ncia a redu??o de MM com a progress?o da DA, sendo mais evidente na transi??o da fase moderada para o grave.
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"A influência do lítio no risco para a doença de Alzheimer" / The influence of lithium on the risk of Alzheimer's diseasePaula Villela Nunes 10 March 2006 (has links)
O lítio é freqüentemente utilizado no tratamento do Transtorno Bipolar, doença associada a um risco aumentado para demência. Evidências experimentais sugerem efeitos neuroproterores do lítio. O lítio inibe a amiloidogênese e a fosforilação da proteína tau tanto in vitro como in vivo. Estes são processos importantes na patogênese da doença de Alzheimer. O objetivo este estudo foi a investigação do efeito do lítio na prevalência de Transtorno Cognitivo Leve e doença de Alzheimer em 114 bipolares idosos eutímicos. Todos os sujeitos completaram uma avaliação catamnéstica, psicopatológica e cognitiva que incluía o mini-exame do estado mental (Mini-mental), o teste cognitivo de Cambridge (CAMCOG) e o questionário do informante sobre o declínio cognitivo do idoso (IQCODE). Foi feita uma comparação da prevalência de Transtorno Cognitivo Leve e doença de Alzheimer entre pacientes em uso de lítio e pacientes em uso de outros estabilizadores de humor. Os sujeitos que entraram na pesquisa tinham em média 68,2 ± 5,0 anos e preenchiam os critérios da Décima Revisão da Classificação Internacional de Doenças e Problemas de Saúde Relacionados (CID-10) para o transtorno bipolar. Durante a avaliação os bipolares estavam eutímicos. Eutimia foi definida como uma pontuação máxima de 7 pontos na escala de Hamilton de 21 pontos para Depressão e 4 na escala de Young para mania. 66 pacientes em uso contínuo do lítio por 6 anos em média foram comparados com 48 pacientes em tratamento com outros estabilizadores de humor. O diagnóstico de Transtorno Cognitivo Leve foi feito de acordo com os critérios de Petersen(1999) e de doença de Alzheimer de acordo com o critério do National Institute for Communicative Disorders and Stroke - Alzheimers Disease and Related Disorders Association (NINCDS/ADRDA). A prevalência de demência nesta amostra (19,4%) foi mais elevada do que o esperado para uma população comparável (7,1%). A prevalência de doença de Alzheimer entre aqueles com lítio foi 4,5% quando comparada com 33,3% entre aqueles sem lítio. Controlando idade e outras variáveis relacionadas ao curso da doença, o efeito do lítio na prevalência de doença de Alzheimer permaneceu significativo (OR = 0,079; p < 0,001). Nenhuma associação foi encontrada com Transtorno Cognitivo Leve. A alta da prevalência de doença de Alzheimer neste estudo está de acordo com as evidências de risco aumentado para demência em pacientes bipolares. Nesta amostra o tratamento com lítio reduziu a prevalência de Alzheimer aos níveis da população idosa em geral. Estes achados estão de acordo com os efeitos neuroprotetores do lítio em eventos cruciais para a patologia da doença de Alzheimer. Estudos prospectivos são necessários para avaliar se o lítio também pode ser efetivo na prevenção de doença de Alzheimer em outras populações. / Lithium is widely used in the treatment of bipolar disorder, a condition associated with an increased risk for dementia. Experimental evidence suggests that lithium has a neuroprotective effect. Both in vitro and in vivo, lithium inhibits amyloidogenesis and phosphorilation of tau protein, which are two crucial processes in the pathogenesis of Alzheimers disease. The objective of this study was to investigate the effect of lithium on the prevalence of Mild Cognitive Impairment and Alzheimers disease in 114 elderly euthymic bipolar patients. Subjects completed a thorough catamnestic, psychopathological and cognitive tests evaluation including the Mini-mental state evaluation, Cambridge cognitive test (CAMCOG) and the informant questionnaire on cognitive decline in the elderly (IQCODE). The prevalence of Mild Cognitive Impairment and Alzheimers disease between patients on lithium therapy and patients on treatment with other mood-stabilizing drugs was compared. Patients were 68.2 ± 5.0 years old and fulfilled of the International Classification of Diseases - 10th Revision (ICD-10) diagnosis for bipolar disorder. At the time of the evaluation patients were euthymic, as defined by a maximum score of 7 in the 21-item Hamilton Rating Scale for Depression, and 4 in the Young Mania Rating Scale. Sixty-six patients were continuously being treated with lithium for six years, on average, and 48 patients were receiving other mood-stabilizing drugs. Diagnosis of Mild Cognitive Impairment was made according to Petersen (1999) and of Alzheimers disease was made according to the National Institute for Communicative Disorders and Stroke - Alzheimers Disease and Related Disorders Association (NINCDS/ADRDA) criteria. The overall prevalence of dementia in our sample (19.4%) was higher than the prevalence expected in the age-comparable general population (7.1%). The prevalence of Alzheimers disease among lithium users was 4.5% as compared to 33.3% among non-users. After controlling for age and other variables related to the clinical course of the bipolar disorder, the effect of lithium on Alzheimers disease prevalence remained significant (OR = 0.079; p < 0.001). No association was found with Mild Cognitive Impairment. The higher prevalence of Alzheimers disease in our study supports the reports of increased risk for dementia in bipolar patients. In our sample, lithium treatment reduced the prevalence of Alzheimers disease to the levels of the general elderly population. This finding is in line with the neuroprotective effects of lithium on crucial events for the pathology of Alzheimers disease. Further prospective studies are needed to clarify whether lithium may also be effective in the prevention of Alzheimers disease in the general population.
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Untersuchung genetischer und geschlechtlicher Einflüsse in der Alzheimerpathologie anhand des Maustiermodells 5XFAD / Research on genetic and gender effects concerning the Alzheimer´s disease based on the mouse model 5XFADKratz, Sebastian 29 November 2010 (has links)
No description available.
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Polymeric nanoparticles as original theranostic approach for alzheimer‟s diseaseBrambilla, Davide 11 January 2012 (has links) (PDF)
The proof of concept of an original nanotechnology-based theranostic approach for Alzheimer‟s disease has been explored. Novel fluorescently tagged nanoparticles have been designed and employed for internalization and transcytosis studies across a recently developed human in vitro blood-brain barrier model. A small library of polymeric nanoparticles have been designed and their ability to capture the Amyloid β1-42 peptide, considered one of the causes of the Alzheimer‟s disease, has been investigated and quantified using an on purpose designed method.
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Papel protetor do 2-feniletinil-butilterúrio em modelos de dano cognitivo em camundongos e na apoptose em células humanas / Protective role of 2-phenylethinyl-butyltellurium on models of cognitive deficits in mice and on apoptosis in human cellsSouza, Ana Cristina Guerra de 27 March 2013 (has links)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Memory is considered to be a process that has several stages, including acquisition, consolidation and retrieval.
Memory impairment occurs when important synapses are modified. Alzheimer s disease (DA) is the most
common cause of dementia. DA is characterized by cognitive damage, accumulation of the pathogenic
amyloid-β (Aβ) peptide, and cholinergic dysfunction. Moreover, oxidative stress is associated with DA.
Therapies used for dementia are still palliative rather than curative. Consequently, new therapies are urgently
required. Biological effects of tellurium compounds have been studied, leading to a set of interesting and
promising applications. Accordingly, 2-phenylethinyl-butyltellurium (PEBT), an organotellurium compound,
has been reported as antioxidant. The purpose of this study was to characterize PEBT as a promising alternative
for memory improvement and prevention of cognitive deficits, using experimental models of DA in mice.
Initially, the present study was conducted to evaluate the effect of a single oral administration (p.o.) of PEBT at
a dose of 10 mg/kg on memory, employing the step-down inhibitory avoidance task. PEBT administered 1 h
before training, immediately after training or 1 h before the test session of the step-down inhibitory avoidance
task increased the step-down latency time in comparison to the control mice, improving acquisition,
consolidation, and retrieval of memory, respectively. The glutamate uptake, but not glutamate release, by
cerebral cortex and hippocampal slices of mice was inhibited after 1 h of treatment with PEBT. After 24 h of
PEBT exposure, the inhibition of cerebral cortex glutamate uptake disappeared. The improvement of memory
by PEBT seems most likely to be mediated through an interaction with the amino acid transporters of the
glutamatergic system. Thereafter, a subchronic PEBT treatment (1 mg/kg, p.o., for 10 days) after injection of
Aβ(25-35) (3 nmol/3 μl/per site, intracerebroventricular) reversed Aβ-induced learning and memory deficits in
the Morris water maze and step-down inhibitory avoidance tasks. In addition, PEBT (10 mg/kg, p.o.),
administered 30 min before scopolamine (1 mg/kg, intraperitoneal), ameliorated memory deficit induced by
this amnesic agent in the Morris water maze. Further, scopolamine was given 30 min before training and test or
immediately post-training of step-down inhibitory avoidance task, inducing damage on acquisition, retrieval,
and consolidation of memory, respectively. PEBT, administered 30 min before scopolamine, improved
consolidation and retrieval stages, but not acquisition. General locomotor and exploratory activities, evaluated
in the open-field test, were similar in all mice. Finally, the antiapoptotic effect of PEBT was evaluated. Human
retinal pigment epithelial cells (ARPE-19 cell line) were exposed to in vitro oxidative stress by 10 ng/ml tumor
necrosis factor-α and 600 μM H2O2. One hour PEBT incubation at concentrations of 7.5 and 10 μM attenuated
the apoptosis induced by oxidative stress. This effect lasted up to 6 hours after oxidative stress induction. PEBT
(5 and 10 μM) inhibited oxidative stress-induced poly (ADP-ribose) polymerase (PARP) cleavage and restored
extracellular-signal-related kinase (ERK) phosphorylation decreased by oxidative stress. The protective
mechanism exerted by PEBT against oxidative stress may involve PARP cleavage, regulation of ERK pathway,
as well as its known antioxidant properties. In conclusion, the finds of the present thesis point out the
ameliorative effect of PEBT on memory stages (acquisition, consolidation and retrieval). Likewise, PEBT
improved memory impairment in mice. These effects seem to be due to strengthen the physiological
glutamatergic tonus by PEBT and the antiapoptotic effect of PEBT. Therefore, PEBT could be considered a
candidate for the prevention of memory deficits such as those observed in DA. / memória inclui pelo menos três tipos de processamento relacionados entre si: aquisição, consolidação e
evocação. A memória é afetada quando as sinapses encarregadas de fazer ou evocar memórias encontram-se
alteradas. A doença de Alzheimer (DA) é a causa mais comum de demência. A DA é caracterizada por danos
cognitivos, acúmulo de peptídeo β-amiloide (Aβ) e disfunção colinérgica. Além disso, o estresse oxidativo está
associado à DA. Uma vez que ainda não há cura para a DA e as terapias atuais são apenas paliativas, torna-se
importante a busca de novos compostos para melhorar danos cognitivos. Com o estudo dos efeitos biológicos
de compostos de telúrio, muitas aplicações estão sendo descobertas. Neste sentido, o composto orgânico de
telúrio 2-feniletinil-butiltelúrio (PEBT) apresenta efeito antioxidante. O objetivo deste estudo foi caracterizar o
PEBT como uma alternativa promissora para a melhora e prevenção de danos cognitivos, usando modelos
experimentais da DA em camundongos. Primeiramente, avaliou-se o efeito de uma única dose oral (p.o) de
PEBT (10 mg/kg) na memória, utilizando a tarefa da esquiva inibitória. O tratamento com PEBT 1 h antes do
treino, imediatamente após o treino ou 1 h antes do teste da esquiva inibitória aumentou a latência comparada
com os animais controles, melhorando a aquisição, consolidação e evocação da memória, respectivamente. A
captação de glutamato, mas não a liberação deste neurotrasmissor, foi inibida em córtex e hipocampo de
camundongos após 1 h de tratamento com PEBT. Após 24 h, a inibição da captação de glutamato no córtex não
foi mais evidenciada. A melhora da memória causada pelo PEBT parece ser mediada através da interação com
os transportadores de glutamato. Além disso, o tratamento subcrônico com PEBT (1 mg/kg, p.o., por 10 dias)
após a injeção de Aβ(25-35) (3 nmol/3 μl/per site, intracerebroventricular) reverteu o prejuízo no aprendizado e
na memória causados por Aβ nas tarefas do labirinto aquático de Morris e na esquiva inibitória. O PEBT (10
mg/kg, p.o.), adminstrado 30 min antes da escopolamina (1 mg/kg, intraperitoneal), também protegeu do dano
de memória causado por este agente anticolinérgico no labirinto aquático de Morris. Quando a escopolamina
foi administrada 30 min antes do treino ou teste, ou imediatamente após o treino da esquiva inibitória houve
dano na aquisição, evocação e consolidação da memória, respectivamente. O PEBT, administrado 30 min antes
da escopolamina, protegeu do dano na consolidação e evocação da memória, mas não na aquisição. Não houve
diferença nas atividades locomotora e exploratória dos animais tratados com o PEBT no teste do campo aberto.
Finalmente, o efeito antiapoptótico do PEBT foi avaliado. Células do epitélio pigmentado da retina humana
(linhagem ARPE-19) foram expostas ao estresse oxidativo induzido pelo fator de necrose tumoral-α (10 ng/ml)
e H2O2 (600 μM). O PEBT (7.5 e 10 μM), quando pré-incubado por 1 h, protegeu contra a apoptose induzida
pelo estresse oxidativo e este efeito permaneceu até 6 h após a indução. O PEBT (5 e 10 μM) inibiu a clivagem
da poli(ADP-ribose) polimerase (PARP) induzida por estresse oxidativo e, também, restaurou a fosforilação da
quinase regulada por sinal extracelular (ERK). O efeito protetor do PEBT contra o estresse oxidativo parece
envolver a clivagem da PARP e a regulação da fosforilaçao de ERK, além de sua atividade antioxidante. Nesse
sentido, os resultados apresentados nesta tese destacam o efeito do PEBT na melhora das três fases da
memória, bem como em modelos de dano cognitivos em camundongos. Estes resultados parecem estar
relacionados ao aumento do tônus glutamatérgico causado pelo PEBT e seu efeito antiapoptótico. Assim sendo,
estes dados sugerem que o PEBT poderá, futuramente, ser considerado candidato para a prevenção de danos de
memória, como aqueles observados na DA.
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Využití koordinované rehabilitace v domově se zvláštním režimem / The use of coordinated rehabilitation in a home with special regimeRATHOVÁ, Lucie January 2018 (has links)
The aim of this diploma thesis is to identify options of how to use the systém of coordinated rehabilitation in a home with a special regime. To obtain information I used qualitative research methodology. Semi-standardized interviews served as the research tool. These interviews were carried out with 10 employees of a home with a special regime run by the City Institute of Social Services in Strakonice. The thesis is divided into a theoretical and a practical part. The theoretical part of the diploma thesis focuses on coordinated rehabilitation as a whole, further, it discusses the individual parts of coordinated rehabilitation. Other chapters describe the most frequent client diagnoses within the Home with a special regime, and finally the standards of social service quality are mentioned. The main research question: What are the options of using coordinated rehabilitation in a home with a special regime? Partial research question: Are employees informed about the options of coordinated rehabilitation? For the purposes of the interview I used questions focused on general identification data, questions focusing on the importance of coordinated rehabilitation, multidisciplinary team. Further, I asked about the individual components of coordinated rehabilitation, and finally, how individual planning is carried out. The result of this diploma thesis is a finding that individual components of coordinated rehabilitation are not fully mutually connected. It would be useful to provide employees with suitable courses to complete their missing knowledge. This diploma thesis might serve as a tool for improving care in the Home with a special regime, it might contribute to the Home with a special regime´s employer awareness of coordnated rehabilitiation, and connect it with practice.
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Disseleneto de p-metoxi fenila atenua o prejuízo cognitivo e a injúria cerebral em um modelo da doença de alzheimer em roedores / P,p -methoxyl-diphenyl diselenide attenuates the cognitive impairment and the brain injury in a sporadic dementia of alzheimer's type in rodentsPinton, Simone 17 September 2012 (has links)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Alzheimer s disease (AD) is a progressive neurodegenerative disorder, mainly characterized by memory and intellectual capacity loss. AD is characterized by deposition of amyloid-β peptide, neurofibrillary tangles, neuroinflammation, energy metabolism impairment, oxidative stress and synaptic dysfunction and loss. Its multiple pathological pathways contribute to the difficulty of AD treatment and prevention. Thus, the development of new therapies for AD curing or treatment is a challenge. The purpose of this study was to indicate an organoselenium moiety, p,p -dimethoxyl-diphenyl diselenide [(MeOPhSe)2], as a promising alternative for the treatment and prevention of sporadic dementia of Alzheimer-type (SDAT), using an experimental model of dementia induced by intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) in rodents. Initially, it was investigated the prophylactic action of (MeOPhSe)2. For this, mice were treated with (MeOPhSe)2 (25 mg/kg, by gavage) and STZ (2μl of 2,5mg/ml solution; i.c.v.) or vehicles, and 48h after that, the treatment was repeated. The tasks of step-down-type passive-avoidance (SDPA), Y-maze and Morris water-maze (MWM), that followed this treatment, showed that (MeOPhSe)2 protected against the impairment in learning and memory caused by i.c.v. injection of STZ in mice. (MeOPhSe)2 protected against the increase in reactive species (RS) and the reduction of glutathione (GSH) levels, as well as modulated the antioxidant enzymes. (MeOPhSe)2 inhibited the acetylcholinesterase (AChE) activity, which was increased by STZ. Subsequently, it was investigated the effectiveness of (MeOPhSe)2 in reversing the cognitive impairment and neuronal damage induced by STZ. Therefore, rats were injected with STZ (1.0 mg/8μl; 4μl/ventricle) twice, 48h apart. After 21 days of STZ injection, regular diet fed rats were supplemented with 10ppm of (MeOPhSe)2 during 30 days. At the end of this period, it was observed that (MeOPhSe)2 dietary supplementation reversed STZ-induced memory impairment in MWM, SDPA and object recognition tasks. The results on SDPA and object recognition tasks demonstrated that the (MeOPhSe)2 improved memory in rats per se. STZ enhanced the RS and protein nitration levels in cortex and decreased GSH levels on hippocampus of rats, (MeOPhSe)2 reversed these alterations. (MeOPhSe)2 normalized AChE activity (which was enhanced by STZ) in both cortex and hippocampus, but did not reverse the deficit in cerebral glucose metabolism (ATP turnover was decrease by STZ). (MeOPhSe)2 was effective in reducing STZ-induced neuronal (apoptosis) loss. Moreover, (MeOPhSe)2 suppressed neuroinflammation induced by STZ in the rats hippocampus. The organoselenium inhibited activation of microglia and astrogliosis. Based on these results, it was concluded that: 1) (MeOPhSe)2 protected and reversed the cognitive abilities decline; 2) the mechanisms involved in the neuroprotective effect of (MeOPhSe)2 are: antioxidant, AChE inhibitor; inflammation suppressor; 3) (MeOPhSe)2 did not alter the energy metabolism; and 4) (MeOPhSe)2 reduced the neuronal death. Therefore, the present study demonstrated that (MeOPhSe)2 is a promising alternative for the drug studies for treatment of cognitive disorders such as SDAT. / A doença de Alzheimer (DA) é uma síndrome neurodegenerativa progressiva caracterizada principalmente por uma perda da memória e da capacidade intelectual. Ela é caracterizada pelo depósito de fragmentos β-amilóides; emaranhados neurofibrilares; neuroinflamação; déficit do metabolismo energético; estresse oxidativo e deficiência da neurotransmissão. As múltiplas vias patológicas da DA dificultam sua prevenção e tratamento. Logo, o desenvolvimento de novas terapias para a DA é um desafio. Por esta razão, este trabalho procurou apontar uma nova molécula orgânica contendo selênio, o disseleneto de p-metoxi fenila [(MeOPhSe)2], como uma alternativa promissora para o tratamento e prevenção da demência decorrente da DA (DEDA), usando um modelo experimental de demência induzida pela injeção intracerebroventricular (i.c.v.) de estreptozotocina (ETZ) em roedores. Inicialmente, avaliou-se o efeito profilático do (MeOPhSe)2. Para tal, camundongos receberam uma dose oral do organoselênio (25mg/kg, gavage) 30 minutos antes da ETZ (2μl de uma solução 2,5mg/ml), esse procedimento foi repetido 48horas depois. Os testes da esquiva passiva, do labirinto em Y e aquático de Morris, que sucederam esse tratamento, revelaram que o (MeOPhSe)2 protegeu os camundongos do prejuízo cognitivo induzido pela ETZ. O (MeOPhSe)2 protegeu o tecido cerebral do aumento das espécies reativas (ER) e da diminuição dos níveis de glutationa (GSH) induzidos pela ETZ, assim como modulou a atividade de enzimas antioxidantes. O (MeOPhSe)2 inibiu a atividade da acetilcolinesterase (AChE), a qual foi estimulada pela ETZ. Posteriormente, investigou-se a efetividade do (MeOPhSe)2 em reverter o prejuízo cognitivo e os danos neuronais induzidos pela ETZ. Para isso, a ETZ foi injetada nos ratos (1μg/8μl, 4μl/ventrículo) em 0 e 48horas. Passados 21dias, iniciou-se uma suplementação dietética com 10ppm de (MeOPhSe)2 durante 30dias. Ao final deste período, observou-se que o (MeOPhSe)2 restaurou as habilidades cognitivas prejudicadas pela ETZ nos ratos, nos testes do labirinto aquático de Morris, esquiva passiva e reconhecimento do objeto. Os resultados referentes aos testes do reconhecimento do objeto e da esquiva passiva apontaram que o (MeOPhSe)2 melhorou per se a memória dos ratos. A ETZ aumentou os níveis de ER e de nitração de proteínas no córtex e diminuiu os níveis de GSH no hipocampo dos ratos, o (MeOPhSe)2 reverteu estas alterações. O organoselênio inibiu a atividade da AChE (aumentada pela ETZ) tanto no córtex como no hipocampo dos ratos, mas não modulou o metabolismo da glicose (ETZ diminuiu ATP-turnover). O (MeOPhSe)2 evitou a perda neuronal (apoptose) e inibiu os eventos neurodegenerativos (ativação da caspase-3) induzidos pela ETZ. O (MeOPhSe)2 suprimiu a neuroinflamação induzida pela ETZ no hipocampo dos ratos. O organoselênio inibiu a ativação das células gliais e astrócitárias. Baseado nestes resultados, conclui-se que: 1) O (MeOPhSe)2 protegeu e reverteu o declínio das habilidades cognitivas; 2) Os mecanismos envolvidos no efeito neuroprotetor do (MeOPhSe)2 são: antioxidante; inibidor da AChE; supressor da neuroinflamação; 3) O (MeOPhSe)2 não altera o metabolismo energético; e 4) O (MeOPhSe)2 reduziu a morte neuronal. Assim sendo, este trabalho demonstrou que o (MeOPhSe)2 é uma alternativa promissora para o estudo de drogas para o tratamento de desordens cognitivas como a DEDA.
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