Alzheimer s disease is characterized by synaptic alterations and neurodegeneration. Histopathological hallmarks represent amyloidplaques composed of amyloid-beta (Abeta) and neurofibrillary tangles containing hyperphosphorylated tau. To determine whether synaptic changes and neurodegeneration share common pathways we established an ex vivo model using organotypic hippocampal slicecultures from amyloid precursor protein transgenic mice combined with virus-mediated expression of EGFP-tagged tau constructs. Confocal high-resolution imaging, algorithm-based evaluation of spines and live imaging was employed to determine spine changes and neurodegeneration. We report that Abeta but not tau induces spine loss and shifts spine shape from mushroom to stubby through a mechanism involving NMDA receptor (NMDAR), calcineurin and GSK-3beta activation. In contrast, Abeta alone does not cause neurodegeneration but induces toxicity by phosphorylation of wt tau in a NMDAR-dependent pathway. We show thatGSK-3beta levels are elevated in APP transgenic cultures and that inhibiting GSK-3beta activity or use of phosphorylation-blocking tau mutations prevent Abeta-induced toxicity of tau. FTDP-17 tau mutants are differentially affected by Abeta. While R406W tau shows increased toxicity in the presence of Abeta, no change is observed with P301L tau. While blocking NMDAR activity abolishes toxicity of both wt and R406W tau, the inhibition of GSK-3beta only protects against toxicity of wt tau but not of R406W tau induced by Abeta. Tau aggregation does not correlate with toxicity. We propose that Abeta-induced spine pathology and tau-dependent neurodegeneration are mediated by divergent pathways downstream of NMDA receptor activation and suggest that Abeta affects wt and R406W tau toxicity by different pathways downstream of NMDAR activity.

ZIEL Als Ursache für die sporadische Creutzfeldt-Jakob Krankheit wird eine spontane Konfigurationsänderung des Prionproteins diskutiert. Die Annahme der Beeinflussung fehlgefaltete Proteinketten, welche bei neurodegenerativen Erkrankungen wie der Alzheimer Demenz oder Parkinson vorliegen, auf die Entwicklung einer zweiten Proteinfehlfaltung stellen eine mögliche Verbindung zwischen dem Auftreten neurodegenerativer Erkrankungen und Prionerkrankungen her. Das Ziel dieser retrospektiven Untersuchung ist es, die klinischen und diagnostischen Eigenschaften von sCJD-Patienten mit Morbus Parkinson oder Demenz in der Familienanamnese zu analysieren um die Diagnostik verbessern zu können. METHODEN Für die vorliegende Arbeit wurde ein Kollektiv aus 133 Patienten mit sicherer oder wahrscheinliche sCJD mit bekannter Ausprägung am Codon-129 rekrutiert. Bei den Geschwistern, den Eltern oder den Großeltern mütterlicher- oder väterlicherseits lag ein Parkinsonsyndrom oder eine dementielle Erkrankung vor. Gegenüber gestellt wurde diesem eine Kontrollgruppe nach Zuordnung nach Geschlecht, Alter (+/- 5 Jahre) sowie PRnP-Codon 129-Genotyp. Der Schwerpunkt der Arbeit liegt auf der klinischen Symptomatik, den Liquorparametern und den Ergebnissen aus bildgebenden Verfahren wie Elektroenzephalographie, zerebraler Computertomographie und Magnetresonanztomographie. ERGEBNISSE Erstes neurologisches Symptom waren zerebelläre Störungen (Ataxie), psychiatrische und visuelle Störungen, während eine dementielle Entwicklung erst im Verlauf hinzutrat. Beim Fortschreiten der Erkrankung wurden Pyramidenbahnzeichen häufiger und extrapyramidale Störungen deutlich seltener diagnostiziert. Insgesamt fiel vom klinischen Erscheinungsbild häufiger die Gruppe FA-Parkinson auf (beispielsweise häufiges Vorkommen von Antriebsstörungen), während FA-Demenz meist der Kontrollgruppe glich. Mit dem Nachweis von PSWC im EEG in 53 % bei FA-Demenz und 61 % bei FA-Parkinson übertrifft die Sensitivität der EEG-Untersuchung nicht die für die sCJD geltende von 64 % (Steinhoff et al. 2004). Mit einem Nachweis der Proteine 14-3-3 im Liquor in 96 % (FA-Demenz) und 100 % (FA-Parkinson) ergibt sich eine ebenso hohe Sensitivität wie für die sCJD bereits postuliert (94 %, Zerr et al. 2000a). Auch die Sensitivität der NSE ist bei den Patienten dieser Arbeit sehr hoch, während der Liquormarker S100b-Protein bei FA-Parkinson-Patienten deutlich seltener den cut-off-Wert erreicht. Ein CJD-typischer MRT-Befund (hyperintense Basalganglien oder kortikale Signalsteigerung) wurde nur in 52 % bei FA-Demenz und bei 49 % bei FA-Parkinson festgestellt. SCHLUSSFOLGERUNG Schließlich lässt sich festhalten, dass bei diesen Patienten nicht vorwiegend eine Demenz wegweisend zur Diagnose ist, sondern auf das Vorliegen zerebellärer oder psychiatrischer Symptome geachtet werden muss. In der Diagnostik kommt dem EEG mit einer hohen Sensitivität eine große Bedeutung zu, während die MRTUntersuchung weniger wegweisend ist. Bei Morbus Parkinson in der Familie unterstützt die Liquoruntersuchung die Diagnostik nicht so stark, während gerade pathologische Werte des Tau-Proteins und des Amyloid-ß 1-42 bei Patienten mit Demenz in der Familie auf eine sCJD hindeuten.

La preuve de concept d‟une approche theranostique pour la Maladie de Alzheimer basée sur les nanotechnologies a été explorée. Des nouvelles nanoparticules polymeriques fluorescentes on été conçus, et leur internalisation et aptitude à traverser un nouveau modèle in vitro de barrière hémato-encéphalique humaine on été étudiées en détails. Une petite librairie de nanoparticules polymerique a été préparés, et leur capacité de capturer le peptide β-Amyloïde1-42, considéré comme une des principales causes de la dégénérescence neuronale, a été évaluées et quantifiées en utilisant une méthode expressément conçus. / 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.

A doença de Alzheimer (DA) é a doença degenerativa cerebral adquirida mais comum e a principal causa de demência nos paises ocidentais. Sua fisiopatologia pode envolver anormalidades neuronais além do processo inflamatório. As infecções odontogênicas são frequentes nestes doentes, e são importantes causas de dor e inflamação crônicas. Os objetivos desta pesquisa foram avaliar as características odontológicas e de dor orofacial de doentes com DA leve comparados aos controles, e verificar aspectos cognitivos, funcionais e emocionais após o tratamento das infecções odontogênicas presentes. Foram avaliados 29 doentes e 30 controles, sendo que os doentes foram tratados e reavaliados posteriormente em dois momentos (após um mês e após seis meses). Foram utilizados os seguintes instrumentos de avaliação: ficha clínica da Equipe de Dor Orofacial; Critérios de diagnóstico em Pesquisa para Disfunção Temporomandibular; questionário de dor McGill; qualidade de vida relacionada à saúde oral (OHIP); avaliação clínica periodontal; índice CPOD-d; índice de placa OLeary; Mini-Exame do Estado Mental (MEEM); escala funcional de Pfeffer. No grupo de estudo, houve maior prevalência de dor orofacial (20,7%, P<0,001), alterações nas articulações temporomandibulares (P<0,05), e infecção periodontal (P=0,002). Após o tratamento, a dor diminuiu (P=0,014), assim como as limitações mandibulares (P=0,011) e os índices periodontais (P<0,05), havendo melhora na qualidade de vida (P=0,009), índice funcional (P=0,001) e índice cognitivo (P=0,048). Como conclusão, a dor orofacial e infecções odontogênicas foram mais comuns em idosos com DA leve do que em idosos saudáveis e seu tratamento resultou em melhora funcional desses indivíduos / Alzheimer\'s disease (AD) is the most common acquired cerebral degeneration and the main cause of dementia in Western countries. Its physiopathology involves neuronal abnormalities and an inflammatory process. Dental infections are frequent in these patients, and important causes of pain and chronic inflammation. The objectives of this research were to evaluate the dental characteristics and orofacial pain of patients with mild AD compared to controls, and to verify cognitive, functional and emotional aspects after the treatment of present oral infections. Twenty-nine patients (29) and 30 controls were evaluated, and the patients were treated and reevaluated in two moments (after one month and after six months). The following instruments were used: clinical questionnaire (Clinical Questionnaire of Orofacial Pain); Research Diagnostic Criteria for Temporomandibular Disorders; McGill Pain Questionnaire; Oral Health Impact Profile (OHIP); periodontal clinical evaluation; DMFT; Plaque index of O´Leary; Mini-Mental State Exam; functional scale of Pfeffer. In the study group, there was a higher prevalence of orofacial pain (20.7%, P<0.001), articular abnormalities at temporomandibular joints (P<0.05) and periodontal infections (P=0,002). After the treatment, the pain reduced (P=0,014), as well as mandibular limitations (P=0.011) and periodontal indexes (P<0.05), and there was an improvement in quality of life (P=0.009), functional index (P<0.001) and cognition (P=0.048). In conclusion, orofacial pain and periodontal infections were more common in patients with mild AD than in healthy subjects and their treatment resulted in better functionality of them

Introdução: O envelhecimento populacional traz desafios, como os prejuízos de funcionalidade em tarefas rotineiras, decorrentes de condições crônicas de saúde, como a demência da doença de Alzheimer (DA). Para elaborar propostas de intervenção adequadas ao portador de DA e a sua família, a funcionalidade deve ser avaliada. O Routine Task Inventory - Expanded (RTI-E) é uma avaliação que permite avaliar o desempenho em ABVD, AIVD, Comunicação e Preparo para o Trabalho a partir da perspectiva do paciente, do cuidador e do terapeuta. Objetivo: Traduzir, adaptar transculturalmente, medir a fidedignidade e a validade da versão brasileira do RTI-E para avaliar a funcionalidade em idosos com DA. Métodos: Realizou-se a tradução e adaptação transcultural do instrumento. Utilizou-se o coeficiente ? de Chronbach para avaliar a consistência interna. A fidedignidade entre avaliadores do RTI-E foi obtida por CCI. A validade de conteúdo foi obtida por validade convergente (correlacionando a avaliações cognitivas e funcionais) e divergente (correlação com HAM-D). A validade de critério foi obtida por validade concorrente. Resultados: Foram avaliados 85 sujeitos, divididos em 42 sujeitos grupo DA (CDR=1 ou 2) e 43 sujeitos grupo controle (CDR=0) e seus pares. Obteve-se a tradução e adaptação transcultural do RTI-E, aprovada pela autora. O RTI-E demonstrou consistência interna elevada em cada escala analisada, sendo o valor mais alto em AIVD obtida por relato do cuidador (?=0,966) e alta fidedignidade entre avaliadores. O instrumento mostrou validade convergente em relação a medidas cognitivas, sendo a maior correlação encontrada em AIVD, relato cuidador (r=0,912, comparado a CAMCOG e r=0,911, comparado a MEEM). Em relação a medidas funcionais, a correlação foi muito forte em relato do cuidador (AIVD X Lawton [r= 0,917]) e em observação do terapeuta (AIVD X DAFS-Br [r=0,911]). As escalas por autorrelato mostram correlações fracas ou insignificantes. O RTI-E mostrou-se capaz de discriminar sujeitos com DA e sem DA, calculando-se áreas sob a curva ROC. Obteve-se pontos de corte variando conforme cada escala. A maior precisão (98,82%) foi encontrada em AIVD, relato cuidador, com sensibilidade 100% e especificidade 97,67%, para ponto de corte 5,26, porém, observando-se todos os valores, nota-se que o RTI-E mostra-se um instrumento mais específico do que sensível. Conclusão: Obteve-se uma versão final adaptada ao nosso meio, aprovada pela autora. O instrumento mostrou-se válido e fidedigno para avaliar a funcionalidade de idosos com DA, oferencendo informações importantes para planejamento de intervenções / Background: Population aging presents challenges, such as functional impairment in routine tasks, due to chronic health conditions, like dementia of Alzheimer\'s disease (AD). In order to design appropriate intervention programs for the AD and his / her family, functionality should be evaluated. The Routine Task Inventory - Expanded (RTI-E) is an assessment that allows evaluating the performance in AVD, IADL, Communication and Working Readiness from the perspective of the patient, the caregiver and the therapist. Objective: To translate, cross-culturally adapt, measure the reliability and validity of the Brazilian version of RTI-E to evaluate the functionality in the elderly with AD dementia compared to the elderly without cognitive impairment. Methods: Translation and cross-cultural adaptation of the instrument was carried out, aiming to maintain semantic and conceptual equivalence to the original. The Chronbach\'s ? coefficient was used to evaluate the internal consistency and interrater reliability was obtained by ICC. Content validity was obtained by convergent validity (correlation with cognitive and functional assessments) and divergent (correlation with HAM-D). Criterion validity was obtained by concurrent validity. Results: There were 85 subjects, divided into 42 subjects, AD group (CDR = 1 or 2) and 43 control group subjects (CDR = 0) and their peers. Translated and cross-culturally adapted version of the RTI-E, approved by the author, was achieved. The RTI-E demonstrated high internal consistency in each analyzed scale, being the highest value in AIVD obtained by a caregiver report (alpha = 0.966) and high interrater reliability. The instrument showed convergent validity in relation to cognitive measures, the highest correlation was found in AIVD, caregiver report (r = 0.912, compared to CAMCOG and r = 0.911, compared to MMSE). About functional measures, the correlation was very strong in caregiver\'s report (AIVD X Lawton [r = 0.917]) and in therapist\'s observation (AIVD X DAFS-Br [r = 0.911]). Self-report scales showed weak or insignificant correlations. RTI-E was able to discriminate between subjects with AD and controls. Cut-off points were obtained varying according to each scale. The highest precision (98.82%) was found in AIVD, a caregiver report, with 100% sensitivity and 97.67% specificity, for cut-off point 5,26. However, observing all values, RTI-E shows to be more specific than sensitive. Conclusion: A final version adapted to our culture, approved by the author was obtained. The instrument was valid and reliable to evaluate the functionality of the elderly with AD, offering important information for planning interventions

A Escala de Avaliação de Demência (Dementia Rating Scale -DRS), proposta por Steven Mattis (1988), tem sido bastante utilizada na avaliação de pacientes com demência tanto na atividade clínica como na pesquisa. Consiste de 5 subescalas: Atenção, Iniciativa/Perseveração, Construção, Conceituação e Memória. Neste estudo, a Escala de Avaliação de Demência foi aplicada em 56 pacientes com doença de Alzheimer com demência de intensidade leve; 55 pacientes com diagnóstico de comprometimento cognitivo leve; e, 60 indivíduos controles. Na diferenciação entre pacientes com doença de Alzheimer e controles a nota de corte de < 128 demonstrou 90,0% de sensibilidade e 89,3 % de especificidade; e, entre pacientes com doença de Alzheimer e comprometimento cognitivo leve, a nota de corte foi < 123 com sensibilidade de 78,2% e 76,8% de especificidade. Na diferenciação entre pacientes com comprometimento cognitivo leve e controles, a nota de corte foi de < 134 com 73,3% de sensibilidade e 72,7% de especificidade. A DRS demonstrou ser um instrumento com boa acurácia diagnóstica na discriminação entre pacientes com doença de Alzheimer de intensidade leve e indivíduos controles. A DRS também foi capaz de diferenciar entre pacientes com comprometimento cognitivo leve de controles, e pacientes com comprometiemnto cognitivo leve de pacientes com doença de Alzheimer de intensidade leve. As subescalas Memória e Iniciativa/Perseveração demonstraram maior acurácia diagnóstica em todas as situações analisadas quando comparadas às demais subescalas. / The Dementia Rating Scale (DRS), proposed by Steven Mattis (1988), it has been very used to assess patients with dementia both in clinical practice and research. Consists of 5 subscales: Attention, Initiation/Perseveration, Construction, Conceptualization and Memory. The Dementia Rating Scale was applied to 56 patients with Alzheimer´s disease, witha dementia of mild intensity; 55 patients with diagnosis of mild cognitive impairment; and, 60 controls. Between patients with Alzheimer´s disease and controls the cutoff score of <128 showed a 90.0% of sensitivity and 89.3% of specificity; and, between patients with Alzheimer´s disease and mild cognitive impairment, the cutoff score was <123 with sensitivity of 78.2% e 76.8% of specificity. In the analysis between patients with mild cognitive impairment and controls, the cutoff score was <134 with 73.3% of sensitivity and 72.7% of specificity. The Dementia Rating Scale showed to be a instrument with good diagnostic accuracy in the discrimination between patients with mild Alzheimer´s disease and controls. The Dementia Rating Scale also was able to discriminated between patients mild cognitive impairment and controls, and between patients with mild cognitive impairment and mild Alzheimer´s disease. The Memory and Initiation/Perseveration subscales showed good diagnostic accuracy in all analysed situations.

Aumento das concentrações de cortisol em idosos com Doença de Alzheimer (DA) tem sido relatado como resultado da ausência de inibição do eixo hipotálamo-pituitária-adrenal (HPA) em decorrência da disfunção hipocampal observada nestes indivíduos. Além disso, associação entre concentrações elevadas de cortisol e comprometimento da memória tem sido evidenciada em idosos saudáveis. Entretanto, pouco se sabe a respeito do envolvimento do estresse nas concentrações de cortisol, no desempenho cognitivo e nas estratégias de coping tanto em idosos saudáveis como naqueles com comprometimento cognitivo leve (CCL) e DA. Assim, este estudo teve o objetivo de investigar a associação entre intensidade de estresse, concentrações de cortisol, estratégias de coping e desempenho cognitivo em idosos saudáveis, com CCL e DA. Para isto, concentrações basais de cortisol salivar foram analisadas em uma amostra composta por 40 idosos saudáveis, 31 idosos com CCL amnéstico e 40 indivíduos com DA leve. O desempenho cognitivo global foi avaliado a partir do mini-exame do estado mental (MEEM), o desempenho da memória através da Bateria Breve de Avaliação Cognitiva (BBAC) e pelo teste de extensão de dígitos na ordem inversa. A intensidade do estresse foi avaliada a partir da Lista de Sintomas de Stress (LSS) e as estratégias de coping através da Escala de Coping de Jalowiec (ECJ). Desta forma, foram observadas concentrações de cortisol marginalmente mais elevadas nos idosos com DA do que nos idosos saudáveis (p = 0.062). Além disso, verificou-se associação positiva entre cortisol e desempenho da memória nos idosos saudáveis (p = 0.008), enquanto correlação negativa entre estas variáveis foi observada no grupo CCL (p = 0.011). Não foi verificada associação significativa nos idosos com DA (p > 0.05). Ademais, observou-se correlação positiva entre as concentrações de cortisol e a intensidade de estresse somente nos idosos com CCL (p = 0.056). Com relação às estratégias de enfrentamento, observou-se que os idosos com CCL que elegem o coping focado no problema apresentam intensidade de estresse menor que os idosos que utilizam o coping focado na emoção (p = 0.048). Estes resultados sugerem que a associação entre concentrações de cortisol, desempenho da memória, intensidade de estresse e coping varia em função da presença ou ausência de comprometimento cognitivo e da percepção das limitações cognitivas / Increased cortisol levels have been reported in elderly with Alzheimers disease (AD) as a result of the lack in the hypothalamic-pituitary-adrenal (HPA) axis inhibition as a function of hipocampal atrophy observed in those subjects. Moreover, association between high cortisol levels and memory impairment has been demonstrated in healthy elderly subjects. However, little is known about the stress involvement in the cortisol levels, in the cognitive performance and in the coping strategies in both elderly with mild cognitive impairment (MCI) and with AD. Thus, this study aimed to investigate the association between stress intensity, cortisol levels, coping strategies and cognitive performance in healthy elderly, subjects with CCL and with DA. Basal salivary cortisol was measured in a sample composed of 40 healthy elderly subjects, 31 individuals with amnestic MCI and 40 subjects with mild AD. Global cognitive performance was evaluated with the Mini Mental State Exam (MMSE) and memory performance was assessed with the Brief Cognitive Screening Battery (BCSB) and the backward digit span test. Stress intensity was evaluated with the Stress Symptoms List (SSL) and coping strategies with the Jalowiec Coping Scale (JCS). Marginally higher cortisol levels were observed in the subjects with AD group in comparison with healthy elderly (p = 0.062). Furthermore, positive association between cortisol levels and memory performance was observed in the healthy elderly (p = 0.008) while negative correlation was observed between these variables in the MCI group (p = 0.011). No significant association was exhibited in the AD group (p > 0.05). Moreover, positive correlation between cortisol levels and stress intensity was observed only in the MCI group (p = 0.056). Regarding the coping strategies, it was observed that those MCI subjects who elect problem focused coping exhibit higher stress intensity than those MCI who use emotion focused coping (p = 0.048). These results suggest the association between cortisol levels, memory performance, stress intensity and coping strategies may vary as a function of the presence or absence of cognitive impairment and as a function of the cognitive deficits awareness

Doentes que apresentam comprometimento cognitivo, como a doença de Alzheimer (DA), podem apresentar maior prevalência de infecções bucais. Entre elas, a periodontite crônica é uma infecção frequente associada ao aumento do nível sérico de marcadores inflamatórios, e recentemente tem sido apontada como um fator que pode relacionar-se à progressão da DA através de seus mecanismos sistêmicos. O objetivo deste trabalho foi verificar a prevalência de infecções bucais e os níveis séricos de IL-1beta, TNF- alfa e IL-6 em doentes com DA, comprometimento cognitivo leve (CCL) e idosos não-demenciados. Foram avaliados 65 idosos (25 com DA, 19 com CCL e 21 saudáveis). A avaliação incluiu o Mini Exame do Estado Mental, Questionário de Atividades Funcionais (Pfeffer), Avaliação Periodontal, índice CPOD, Questionário de Avaliação Clínica Orofacial (EDOF-HC) e avaliação de concentração sérica de IL-1beta, TNF-alfa e IL-6. Os doentes com DA e CCL apresentaram maior quantidade de dentes ausentes e por um período maior de tempo do que os idosos saudáveis (P= 0.038) e a doença periodontal (DP) foi a causa principal das perdas dentárias (P= 0.035). Os doentes apresentaram maior prevalência de candidose do que os controles (P= 0.05). As análises de correlação demonstraram que quanto maior a concentração de IL-6, pior a funcionalidade pelo índice de Pfeffer (P < 0,001; Pearson) e pior o índice cognitivo (P=0,018; Pearson). Por outro lado, quanto maior a concentração de TNF-alfa, piores os índices IS, PCS média e máxima e PCI média e máxima (P < 0,001; Pearson), maior o tempo de uso de próteses (P=0,010; Pearson) e pior o índice de placa O´Leary (P=0,008; Pearson). IL-6 e TNF-alfa se correlacionaram positivamente (P < 0,001; Pearson). Conclui-se que há um aumento sérico de citocinas associado ao comprometimento cognitivo e à doença periodontal. Estudos futuros poderão esclarecer os mecanismos que determinam aumento de IL-6 nas demências e aumento de TNF-alfa nas infecções periodontais e elucidar possíveis associações entre eles / Patients that present cognitive impairment, as Alzheimer´s Disease (AD), may have high prevalence of oral infections. Among them, chronic periodontitis is often associated to the increase of seric inflammatory biomarkers, and it recently has been referred as a factor than can change the progression of AD by its systemic mechanisms. The objective of this study was to investigate the prevalence of oral infections and seric levels of IL-1alfa, TNF-alfa and IL-6 in patients with AD, mild cognitive impairment (MCI) and non demented elderly. Sixty-five elderly were evaluated (21 with AD, 8 with MCI and 15 healthy). The evaluation included the Mini Mental State Exam, Questionnaire of Functional Activities (Pfeffer), periodontal evaluation, DMFT, Clinical Orofacial Questionnaire (EDOF-HC) and seric concentrations of IL-1beta, TNF-alfa and IL-6. The patients with AD and MCI had more absent teeth and for a longer period of time than the healthy elderly (P= 0.038) and periodontal disease (PD) was the main cause of teeth losses (P= 0.035). The patients had higher prevalence of candidiasis than the controls (P= 0.05). The serum level of IL-6 was higher in the patients that showed bad performance in the MMSE (P=0.018; Pearson) and daily life activities - Pfeffer (P < 0.001; Pearson). The TNF-alfa serum level was more elevated when patients had PPD, CAL, BI (P < 0.001; Pearson) and O\'Leary plaque index (P=0.008; Pearson). IL-6 e TNF-alfa were positively correlated (P < 0.001; Pearson). In conclusion, there is a seric increase of cytokines associated with the cognitive impairment and periodontal disease. Future studies are necessary to clarify the mechanisms that underlie the increase of IL-6 in dementias and the increase of TNF-alfa in periodontal infections and possible associations between them

M. Niemann-Pick Typ C (NPC) ist eine juvenile Demenz mit intrazellulärer Anreicherung von freiem Cholesterin, M. Alzheimer (AD) eine senile Demenz, die mit einem Polymorphismus im Gen des Cholesterintransportproteins Apolipoprotein E (ApoE) assoziiert ist. Bei beiden Erkrankungen treten im Gehirn zahlreiche neurofibrilläre Tangles (NFT), bestehend aus Protein Tau, auf. Es sollte mit einer für freies Cholesterin spezifischen Filipin-Färbung herausgefunden werden, ob sich bei beiden Erkrankungen der Cholesteringehalt Tangle-tragender Neurone von dem Tangle-freier unterscheidet. Zur Verfügung standen diverse Teile aus dem Zentralen Nervensystem von 5 NPC- und Gyri temporales superficiales von 9 AD-Fällen. In Material von 3 NPC-Fällen und 1 AD-Fall fanden sich intraneuronale, mit Tangles assoziierte Cholesterinakkumulationen. In 3 AD-Fällen fanden sich außerdem Cholesterinakkumulationen in Assoziation mit Senilen Plaques. Der Cholesteringehalt Tangle-tragender Neurone war in 6 Regionen der NPC-Fälle und in 3 AD-Fällen erhöht. Für alle Neuronenpaare der AD-Fälle insgesamt ergab sich ein erhöhter Cholesteringehalt des Tangle-tragenden Neurons. Cholesterinspeicherung im NPC-Hirn könnte über oxidativen Stress oder eine Veränderung der cholesterinabhängigen Signaltransduktion zur Tangle-Bildung führen. Argumente für die Unterstützung der Tangle-Bildung durch Cholesterin über oxidativen Stress und veränderte Signaltransduktion in AD werden angeführt. Diese Untersuchung erlaubt, neue Hypothesen zu gemeinsamen Mechanismen der Tangle-Entstehung in AD und NPC zu formulieren. / Niemann-Pick type C disease (NPC) is a juvenile dementia with intracellular accumulation of free cholesterol, whereas Alzheimer s disease (AD) is a senile dementia associated with a gene polymorphism of a cholesterol transport protein, apolipoprotein E (apoE). In both conditions, there are abundant neurofibrillary tangles (NFT) in brain, consisting of protein tau. This study addresses the issue whether cholesterol content of tangle-bearing neurons is the same compared to tangle-free neurons, in both diseases. For this purpose, staining with the free cholesterol-specific fluorochrome filipin was used. Several CNS tissue specimen of 5 NPC cases and superior temporal gyri of 9 AD cases were available. In 3 NPC cases and 1 AD case, intraneuronal cholesterol accumulation were found associated with neurofibrillary tangles. Furthermore, cholesterol accumulations were found associated with senile plaques in 3 AD cases. Cholesterol content of tangle-bearing neurons was increased in 6 regions of the NPC cases and in 3 AD cases. For all neurons analysed in AD, the tangle-bearing neuron showed more cholesterol than the adjacent tangle-free neuron. Cholesterol storage in NPC brain could lead to neurofibrillary degeneration by enhancing oxidative stress or by alterating cholesterol-dependent signal transduction. Cholesterol accumulation in AD neurons could lead to neurofibrillary degeneration by the same mechanisms. This study allows the creation of new hypotheses concerning common mechanisms of neurofibrillary degeneration in both Niemann-Pick type C and Alzheimer s diseases.

Im Zentrum der vorliegenden Arbeit steht die Proteomanalyse des APP23-Mausmodells für die Alzheimer-Krankheit (AK). Es wurden die Gehirnregionen Hippocampus und Cortex der Altersstadien Embryonaltag 16 sowie 1, 2, 7 und 15 Monate untersucht und somit erstmals eine Art „Proteom-Lebensprofil“ eines Mausmodells erstellt. Bei dem Vergleich der APP23-Mäuse mit Wildtypmäusen konnte innnerhalb aller untersuchten Altersstadien und Gehirnregionen eine große Anzahl quantitativer Proteinexpressionsunterschiede festgestellt werden. Interessanterweise bestand jedoch im Hippocampus adoleszenter, zwei Monate alter Mäuse, ein herausragend großer Unterschied. Ein Vergleich der Proteomzusammensetzung zwischen den verschiedenen Altersstadien zeigte, dass spezifisch im Hippocampus der adoleszenten APP23-Mäuse viele entwicklungsbedingte Proteomveränderungen ausgeblieben waren. Zusammen mit der Beobachtung, dass in diesem Altersstadium viele synaptische Proteine in den APP23-Mäusen herunterreguliert waren, weisen die gewonnenen Daten darauf hin, dass ein natürlicher Peak in der hippocampalen Plastizität während der Adoleszenzphase in den APP23-Mäusen ausgeblieben war. Es ist weiterhin bekannt, dass APP als auch eine wichtige Rolle in der embryonalen Neurogenese spielt. Da über diese Prozesse noch wenig bekannt ist, wurde im Rahmen der vorliegenden Studie weiterhin eine grundlegende Untersuchung der murinen embryonalen Gehirnentwicklung durchgeführt. Dabei wurde beobachtet, dass innerhalb eines Zeitraums von zwei Entwicklungstagen die Anzahl an quantitativ veränderten Proteinen konstant ist. Dies könnte die maximal mögliche Veränderungsrate wiederspiegeln, die wiederum einen begrenzenden Faktor für die Geschwindigkeit der Embryonalentwicklung darstellt. Weiterhin stieg im Zuge der Neurogenese die Konzentration zelltypspezifischer Proteine an während im Gegenzug die Konzentration unspezifischer Proteine abnahm. / The work presented here focuses on the analysis of the APP23 mouse model for alzheimer´s disease (AK). Using a proteomics approach; the two brain regions cortex and hippocampus, were analyzed at the ages 1,2,7 and 15 months and at embryonic day 16. Thus, for the first time, a lifetime profile of brain proteome alterations caused by mutant APP expression was created. Protein expression alterations between APP23 and control mice were numerous at all age stages but unexpectedly, the hippocampus of two-month old (adolescent) mice, showed a dramatic peak in the number of altered proteins. When comparing proteome patterns longitudinally between age-stages, protein alterations were largely absent in the hippocampus of adolescent APP23-mice but not in other stages compared. Apparently, the large difference in hippocampal protein pattern changes between two-month old APP23- and wildtype-mice was caused by an absence of distinct developmental changes in APP23-mice. In summary, the absence of longitudinal developmental proteome alterations during adolescence, a developmental stage where neuronal plasticity is prominent and horizontal (disease/control) down-regulation of many proteins related to plasticity suggests the disruption of a normally occurring peak of hippocampal plasticity during adolescence of APP23-mice. APP was also suggested to play an important role in embryonic neurogenesis. Since information about the molecular mechanisms of neurogenesis is scarce, a basic analysis of protein changes during normal embryonic neurogenesis was conducted. Interestingly, the rate of protein concentration change within two days of development was constant. This might represent the maximal rate limiting the speed of embryonic development. During neurogenesis, cell-type specific proteins were up- and unspecific proteins down-regulated. In summary, this study shows that it is of utmost importance to investigate AK even at an early age prior to the occurrence of disease symptoms.