La Maladie d’Alzheimer est une maladie multifactorielle dont l’apparition peut être influencée par divers facteurs génétiques ou environnementaux, tels l’allèle ApoEɛ4, différents polymorphismes ainsi que le vieillissement ou la ménopause, par exemple. Depuis une dizaine d’années des études épidémiologiques ont mis en évidence l’existence d’une relation entre le statut métabolique des individus durant leur vie adulte et l’augmentation du risque de développer la MA à un âge plus avancé. Les travaux présentés dans cette thèse visent à étudier l’impact d’un régime riche en graisse, permettant le développement d’une obésité, sur le développement physiopathologique d’un modèle transgénique mimant le versant Tau de la MA, la souris THY-Tau22. Cette souris surexprime dans les neurones du cerveau la protéine Tau humaine mutée en 2 sites favorisant sa phosphorylation et son agrégation et présente une pathologie Tau hippocampique évolutive qui s'exprime en parallèle d'altérations mnésiques. Ainsi, ce modèle murin constitue un modèle particulièrement adapté à l'étude des conséquences comportementales, anatomo-pathologiques, biochimiques et transcriptomiques de la tauopathie de la MA. L'induction d'une obésité et de ses conséquences métaboliques chez la souris THY-Tau22 de 7 mois a engendré une diminution des performances d'apprentissage accompagnée d'une aggravation de la pathologie Tau hippocampique. De façon intéressante, ces modifications pathologiques ont eu lieu en parallèle du maintien d'une bonne sensibilité à l'insuline périphérique et en présence d'une activation de la voie de signalisation du récepteur à l'insuline dans l'hippocampe. Ces données remettent en cause le dogme établit dans la littérature, et suggèrent que les conséquences délétères d'une obésité sur Tau dans la MA peuvent être dissociées d'une résistance à l'insuline périphérique et centrale. Sur le plan métabolique, lorsque nourries par un régime obésifiant, les souris THY-Tau22 de 7 mois présentent au contraire de leurs contrôles de portées wild-type une homéostasie glucidique peu détériorée. Afin de contrôler la véracité de ce phénotype nous avons entrepris la caractérisation métabolique de la lignée de souris THY-Tau22 via une étude longitudinale de 2 à 9 mois. Cette caractérisation a permis de mettre en évidence le caractère plus maigre de la souris THY-Tau22 comparé aux WT avec des différences de paramètres métaboliques qui s'accentuent au cours de la vie de la souris THY-Tau22. Afin de décrypter si cette particularité métabolique est le fruit du gain de fonction lié à la surexpression de la protéine Tau dans le cerveau de cette souris, un suivi longitudinal identique a été réalisé chez la souris Knock-out pour le gène Tau (KO-Tau). Les résultats indiquent que la souris KO-Tau présente un phénotype métabolique inverse à celui de la souris THY-Tau22, avec poids corporel augmenté et homéostasie glucidique altérée, suggérant que Tau puisse posséder un rôle dans l'homéostasie métabolique. En conclusion l’ensemble des résultats de cette thèse suggère par conséquent qu'une obésité provoque l'aggravation de la pathologie Tau de la MA, et ce, en l'absence d'une résistance à l'insuline. De plus, nous révélons l'existence d'une potentielle fonction inédite de la protéine Tau dont l'action au niveau central aurait des conséquences métaboliques périphériques. / Alzheimer's disease (AD) is a multifactorial disease that can be influenced by several genetic or environnemental factors, such as ApoEɛ4 allele, genetic polymorphisms and ageing and menopause, for instance. Since a decade epidemiological studies have pointed out the existence of a relationship between the metabolic status of individuals during their adult's life and an increased risk of developing AD at an advanced age. Indeed, type 2 diabetes doubles the risk to have AD. Mid-life overweight and obesity are also important risk factors for the development of AD. The work presented in this thesis aim at studying the impact of an obesity induced by a high-fat diet on physiopathological development of a transgenic mouse model reproducing AD-like Tau pathology, the THY-Tau22 mouse. This mouse overexpresses in the neurons a human Tau protein, mutated on two sites favoring its phosphorylation and aggregation and exhibits a progressive hippocampal Tau pathology in parallel with learning and memory impairment. This mouse model therefore constitutes an appropriate model to study the behavioral, anatomo-pathologic, biochemical and transcriptomic consequences of AD-like Tauopathy. Diet induced obesity and its metabolic disturbances in 7 months THY-Tau22 mice impaired learning and induced an aggravation of hippocampal Tau pathology. Interestingly, this pathological worsening occurred in parallel with healthy peripheral insulin sensitivity and activation of central insulin signaling. These data question the current dogma of the literature and suggest that deleterious consequences of obesity on Tau pathology could happen dissociated from peripheral and central insulin signaling. On the metabolic point of view, when fed high-fat, 7 months THY-Tau22 mice present, on the contrary of their littermate controls, a relative healthy glucose homeostasis. To control this phenotype we undertook the characterization of THY-Tau22 mice with a longitudinal study from 2 to 9 months. This characterization led us to underscore the leaner phenotype of THY-Tau22 compared to their WT counterparts, with increasing differences in metabolic parameters over age. In order to decipher if this metabolic feature is due to a gain of function induced by the neuronal overexpression of Tau we realized the same phenotyping on a Tau knock-out mouse (KO-Tau). The results indicate that, in contrary to THY-Tau22 mice, KO-Tau mice present a mirrored metabolic phenotype with higher body weight and impaired glucose homeostasis, suggesting a possible role for Tau in metabolic homeostasis. In conclusion, all the data presented in this thesis therefore suggest that obesity induces a worsening of AD-like Tau pathology that occurs dissociated from insulin resistance. Moreover, our study reveals the existence of a potential unpublished function of Tau protein whose action at central level could have peripheral metabolic consequences.

La maladie d'Alzheimer est la maladie neurodégénérative la plus fréquente dont la prévalence augmente avec l'âge. Elle résulte d'un excès de peptide β-amyloïde (Aβ) capable de s'agréger, de s'insérer dans la membrane plasmique des cellules et de s'organiser en pores perméables au calcium. Cette insertion est modulée par la composition lipidique de la membrane dont le cholestérol. Alors que plusieurs études indiquent que le cholestérol interagit avec le peptide Aβ et module sa toxicité, les mécanismes moléculaires sous-jacents demeurent mal compris.A l'aide d'approches expérimentales multiples nous avons évalué le rôle du cholestérol dans l'insertion du peptide Aβ à la membrane ainsi que dans le processus d'oligomérisation responsable de la formation de pore. Notre étude identifie le domaine 22-35 du peptide Aβ comme domaine d'interaction avec le cholestérol au sein duquel deux acides aminés sont essentiels : la Val24 et la Lys28. Ce petit fragment s'organise en pore dans la membrane plasmique et déclenche une entrée massive de calcium dans les cellules. Cet effet n'est plus observé lorsque les cellules ont moins de cholestérol dans leur membrane ou en présence de zinc, un inhibiteur des pores amyloïdes. Le cholestérol maintient le peptide de façon oblique et en hélice α. Cette orientation favorise l'établissement d'une liaison hydrogène entre l'Asp27 d'un peptide et la Lys28 d'un peptide voisin, qui stabilise le pore. Enfin, notre étude montre que le bexarotène, un composé anti-Alzheimer dont le mécanisme d'action est controversé, prévient l'insertion du peptide dans des membranes et empêche la formation de pores dans la membrane plasmique des cellules nerveuses. / Alzheimer's disease is the most common neurodegenerative disease whose prevalence increases with age. It is the result of excess β-amyloid peptide (Aß), which self-organizes. This peptide is able to insert into the plasma membrane of cells where their organization in calcium permeable pores triggers the early stages of toxicity. This insertion is directly modulated by the lipid composition of the membrane especially cholesterol. Whereas several studies indicate that cholesterol interacts with and modulates Aß toxicity, the underlying molecular mechanisms remain poorly understood.Using computational, physico-chemical and cellular approaches, we evaluated the role of cholesterol in the insertion of the Aß peptide in the membrane and in the oligomerization process responsible for pore formation. Our study identifies the 22-35 fragment of Aβ as a functional cholesterol-binding domain in which two amino acids are essential: Val24 and Lys28. When incubated with SH-SY5Y cells, the minimal Aβ22-35 peptide caused an increase of Ca2+ entry. This effect was no longer observed in cholesterol-depleted cells and was inhibited by zinc, a classical blocker of amyloid channels. Cholesterol specifically induced a tilted alpha-helical topology of Aβ22-35 which appeared to facilitate the oligomerization process through the establishment of a hydrogen bond network involving Asn27 and Lys28. Finally, our study showed that bexarotene, an anti-Alzheimer compound whose mechanism of action is still under debate, competitively inhibited Aβ insertion into cholesterol-containing membranes and prevented calcium-permeable amyloid pore formation in the plasma membrane of neural cells.

Le diagnostic différentiel de Démence Fronto-Temporale (DFT) vs Maladie d’Alzheimer (MA) n’est pas toujours facile à établir, et peuvent être confondus avec ceux de l’Aphasie Primaire Progressive (APP) » (Snowden et al. 2011) puisque l’anomie est présente dans les deux pathologies (Assal et al. 2009, Barkat-Defadas et al. 2008, Léger et al. 2007). La MA peut se décrire comme une démence dégénérative, avec une perte de tissu neuronal plutôt dans les lobes pariétal et temporal, résultant dans des difficultés dans les domaines de l’attention, les fonctions exécutives, la mémoire, les compétences pour apprendre, le langage, le calcul, et les fonctions viso-spatiales (Robin et al. 2003). De l’autre coté, la DFT est une démence qui atteint plutôt les lobes frontal et temporal elle peut se classifier d’après trois variantes: variante comportementale (DFTbf), Aphasie primaire progressive (APP) et démence sémantique (DS) (Kertesz et al 2003). Dans les deux cas nous pouvons trouver des troubles communs du à la perte du tissu dans les régions temporales, dans les étapes initiales de la maladie. L’analyse du langage chez des patients avec DFT et MA, et la corrélation de celui-ci avec le profil psycholinguistique permettra l’isolement des caractéristiques cliniques propres du profil des patients, a fin de proposer des critères plus spécifiques pour disjoindre le profil clinique de langage entre la DFT et la MA.La présente thèse sera réalisée en co-tutelle entre l’hôpital San Ignacio / Pontificia Universidad Javeriana et l’Université Lumière-Lyon2. Ce projet poursuit trois objectifs : (i) recueillir des données psycholinguistiques et de langage (tenant compte des années de scolarité et la sévérité du cours de la maladie), (ii) étudier et isoler les variantes linguistiques, qui peuvent influencer erronément la différence des critères de diagnostique entre la DFT et MA; (iii) raffiner les critères de diagnostique de la DFT et MA. 75 sujets ont été évalués (FTD n = 63, AD = 12, 22 sujets contrôles). Le test d'afastie (BAT) (Paradis 1989) a été utilisé pour identifier la discrimination auditive, la compréhension des structures syntaxiques (auditive et lecture), la production de phrases, la compréhension des narrations, la lecture de phrases, ainsi qu'une analyse des erreurs selon la structure syntaxique. En outre, nous évaluons les fonctions exécutives et les tests cognitifs de base. Les échantillons de parole spontanée ont été transcrits en utilisant le format CHAT et analysés à l'aide des programmes CLAN. En adition aux analyses descriptives, une analyse de proximité des distances euclidiennes au carré a été effectuée ainsi que des corrélations et régréssions.Les résultats montrent que patients atteints de PPA ont eu la pire performance dans la plupart des tâches langagières. Les DFTvf montrent une bonne peormance pour les tâches standardisées, mais montrent des difficultées isolées pour la compréhension de structures syntaxiques de type négatif qui peut s’associer à l'incapacité de représenter une séquence temporelle de la phrase. Les résultats démontrent que le discours spontané nous permet de différencier tous les groupes de patients. Le discours de ces patients peut être distinctif et reflète non seulement les capacités linguistiques du sujet, mais aussi les autres fonctions cognitives. Même si la théorie différencie les groupes PPA selon leur fluence, les résultats montrent qu’avec les variables qui portent sur la fluence de la parole qu'il n'est pas possible de différencier la variante non fluente et la logopénique. D'autres variables telles que les erreurs et la grammaire doivent être incluses dans les analyses pour obtenir le diagnostic différentiel des variantes de la APP. La parole spontanée démontre être un outil inestimable dans la pratique quotidienne du clinicien pour les diagnostics précoces et les critères pour un diagnostic différentiel entre la MA et la DFT – et ces trois variantes-. / Even though the large majority of cortical dementia is of the Alzheimer’s disease type, there are differential diagnosis limitations of current diagnostic criteria for early-onset Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD, all three variants: behavioural variant frontotemporal –FTDbv-, Primary progressive aphasia –PPA- and semantic dementia –SD-). Initially, either AD and FTD share cognitive declines and first complain includes memory and no language in FTLD or language and no memory in AD. For instance, word retrieval deficits are common in AD and are thought to reflect a degradation of semantic memory. Yet, the nature of semantic deterioration in AD and the underlying neural correlates of these semantic memory changes remain largely unknown (Wierenga, 2011). On the other hand, PPA, FTDbv and SD have, as well, common behavioural features: PPA, prior to word loss, may show apathy and semantic dementia patients have, long before, the pure meaning loss, a great decline on emotional and conduct process. Since new guidelines for the differential diagnosis of behavioural FTD (Raskovsky, 2011) and selective language features –nonfluent/agrammatic, semantic, syntax, narrative - of the language variants are being revised (Gorno-Tempini, 2011) the present project present a novel way to define criteria regarding cognition profile through language analysis in all: AD and FTDL all variants. In sum, isolation of pure clinical characteristics in order to enriched the clinic profile and subtract the pure linguistic features will facilitate better common clinical compromise besides language differences (Zanini et al. 2011, Hernández et al. 2011, Ardila& Ramos, 2008). The present study aims to study through the Javeriana University Memory Clinic (PUJMC) at the San Ignacio Hospital in Colombia, based on the experience in the last 14 years where almost 3000 patients have been studied, language semiology between AD, FDT – all three variants. This project has three objectives: (i) to collect psycholinguistic and language data (taking into account the years of schooling and the severity of the course of the disease), (ii) study and isolate linguistic variants that may erroneously influence the difference in diagnostic criteria between DFT and MA; (iii) refining the diagnostic criteria for FTD and MA. 75 subjects were assessed (FTD n= 63, AD= 12, 22 control sample subjects). Bilingual Aphasia Test (BAT) (Paradis 1989) was used in order to identify auditory discrimination, syntactic structures comprehension (auditory and by reading), sentences production, auditory and by reading, comprehension of narrative structures, sentences reading, as well as an analysis of errors according to the syntactic structure. Additionally, we assess executive functions and basic cognition battery. Spontaneous speech samples were transcribed using the CHAT format, and analysed using the CLAN programs Besides a descriptive analysis, a hierarchical clustering through a squared Euclidean distances was done, where patients groups were formed by similar clinical neighbors regardless the FTD variant. Results show that deep language analysis is useful when heterogeneity w/groups is present and depends (in all groups) on the disease stage. PPA patients had the worse performance. bvFTD executive passive structure difficulty is associated with executive functions: The inability to represent a temporal sequence of the phrase –not understanding if.. Then). Results demonstrate that spontaneous speech allow us to differentiate between all groups of patients. Discourse of these patients can be distinctive and it reflects not only the subject's linguistic abilities but other cognitive functions as well....

<p>Alzheimer’s disease (AD), is a devastating neurodegenerative disorder that destroys the patient’s ability to perform daily living task and eventually, takes their lives. Currently, there are 5.8 million people in North America that suffer from AD. This number is projected to by 13.8 million by the year of 2050. For many years, researchers have been dedicated on performing automated diagnosis based on neuroimaging. There are critical needs in two aspects of AD: 1) computer-based AD classification with MRI images; 2) computer-based tools/system to enhance the AD patient’s quality of life. We are addressing these two gaps via two specific objectives in this study.</p> <p>For objective 1, the task is to develop a machine-learning based intelligent model for classification of AD conditions (Normal Control [NC], Mild Cognitive Impairment [MCI], Alzheimer’s disease [AD]) based on MRI images. Specifically, four different deep learning models were developed and assessed. The overall average accuracy for AD classification is 81.5%, provided by Multi-Layer-Output model.</p> <p>For objective 2, a deep learning model was developed and evaluated to recognitze three specific type of indoor scenes (bedroom, living room and dining room). An accuracy of 97% was obtained.</p> <p>This study showed the potential of application in deep learning models for two different aspects of AD - disease classification and intelligent model-based assistive device for AD patients. Further research and development activities are recommended to further validate these findings on larger and different datasets.</p>

A doença de Alzheimer (DA) é caracterizada pela perda progressiva de memória episódica relacionada à agregação do peptídeo ?-amiloide (A?) e à fosforilação anormal da proteína tau, levando à perda da função colinérgica. É bem conhecido que o comprometimento desta função devido à neurotoxicidade do peptídeo A? contribui significativamente para o declínio cognitivo associado à DA. Os inibidores da enzima acetilcolinesterase (AChE) compõem a principal classe de drogas usadas no tratamento da DA. No entanto, há uma grande necessidade de síntese de novas moléculas, uma vez que os fármacos já em uso pelos pacientes apresentam alta toxicidade hepática, além de vários efeitos colaterais devido à ação nos tecidos periféricos. A hipótese do presente projeto se baseia na atividade de indução de neurodiferenciação e neuritogênese de novos compostos inibidores de AChE, os quais são híbridos sintéticos de donepezila-tacrina, além de atuarem como neuroprotetores em culturas de células neuronais, sob condições experimentais de um estímulo neurotóxico e de estresse oxidativo induzidos pelo peptídeo A?(1-42) e peróxido de hidrogênio (H2O2). Assim, o objetivo deste trabalho foi avaliar a capacidade de neurodiferenciação e neuritogênese, assim como o potencial neuroprotetor de duas moléculas híbridas de donepezila-tacrina na linhagem SH-SY5Y, modelo de diferenciação neuronal. Foram realizados ensaios de citotoxicidade e hepatotoxicidade em células tratadas e coletadas em diferentes tempos (24, 48, 72 e 120 h) nas linhagens celulares SH-SY5Y e HepG2, respectivamente. Ensaios de diferenciação neuronal (análise morfológica), expressão proteica, cinética ciclo celular, proliferação celular, alterações mitocondriais e de estresse oxidativo foram realizados em linhagem neuronal SH-SY5Y. Ainda, foram realizados ensaios de viabilidade e morte celular para avaliar a capacidade de neuroproteção dos novos compostos híbridos na linhagem SH-SY5Y. Estes não se mostraram citotóxicos e não alteraram a viabilidade celular em todas as concentrações avaliadas: TA8Amino 0,0035 a 0,112µM e TAHB3 0,088 a 2,84µM; nos ensaios de hepatotoxicidade, o composto TAHB3 reduziu a viabilidade celular na maior concentração (2,84 µM) e no tempo de 24 h. Ambos os compostos híbridos foram capazes de induzir diferenciação neuronal e neuritogênese, cerca de 55% das células para TA8Amino e 43% para TAHB3. Apenas o composto TA8Amino induziu um aumento de aproximadamente 75% na expressão do marcador ?-III-Tubulina comprovando a formação de neurônios maduros. Nenhum dos tratamentos realizados causaram alterações significativas na distribuição das células nas fases do ciclo celular e no ensaio de proliferação celular. O composto TA8Amino foi capaz de induzir a produção de ROS intracelular (48,27%) e mitocondrial (67,60%) nas células diferenciadas. Ambos os compostos híbridos aumentaram a expressão de SOD1, indicando atuação na atividade antioxidante das células. Entretanto, os compostos não alteraram o potencial de membrana mitocondrial e massa mitocondrial. Esses dados demonstram que o estresse oxidativo induzido pelo TA8Amino não gerou danos por disfunção mitocondrial nas células diferenciadas. Na avaliação de alterações da expressão proteica de PTEN(Ser380/Thr382/383), AKT(Ser473) e COX2 ambos os compostos híbridos promoveram a indução de PTEN e AKT. TA8Amino e TAHB3 induziram um aumento na expressão de COX2 demonstrando umapossível atuação na via de sinalização PI3K/AKT/COX2, compatível com a diferenciação neuronal. Nos ensaios de viabilidade celular, os compostos TA8amino e TAHB3 apresentaram efeito de neuroproteção frente ao dano neurotóxico induzido pelo peptídeo A?(1-42), promovendo uma proteção de 91,93% para TA8Amino e 54,68% para TAHB3, embora o mesmo efeito não tenha sido observado nas células tratadas com o peróxido de hidrogênio. Entretanto, a indução de morte por apoptose pelas moléculas híbridas nas células tratadas com o peptídeo A?(1-42) foi apenas levemente alterada pelos compostos, havendo uma redução de 5,10 e 4,85%, respectivamente, para TA8Amino e TAHB3. Em geral, os resultados do presente trabalho demonstraram que os compostos híbridos donepezilatacrina (TA8amino e TAHB3), inibidores da AChE, apresentam vantagens como potenciais fármacos, visto não serem citotóxicos nas concentrações de inibição da enzima AChE, além de serem capazes de induzir diferenciação neuronal, neuritogênese e neuroproteção, diferentemente dos fármacos donepezila e tacrina, testados isoladamente. / Alzheimer\'s disease (AD) is characterized by a progressive loss of episodic memory related to aggregation of ?-amyloid peptide (A?) and to abnormal phosphorylation of tau protein, leading to loss of cholinergic function. It is well known that the impairment of this function due to A? peptide neurotoxicity contributes significantly to the cognitive decline associated with AD. Acetylcholinesterase (AChE) inhibitors are the main class of drugs used to treat AD. However, there is a great need for synthesis of new molecules, since current drug treatment presents high hepatic toxicity, besides several side effects due to the action in the peripheral tissues. The hypothesis of this project is based on the activity of AChE inhibitor compounds (synthetic hybrids of donepezil-tacrine) in terms of inducing neurodifferentiation and neuritogenesis, as well as neuroprotective effects in neuronal cells under experimental conditions of a neurotoxic stimulus and oxidative stress induced by the peptide A? (1-42) and hydrogen peroxide (H2O2). Thus, the objective of this work was to evaluate the neurodifferentiation and neuritogenesis abilities, as well as the neuroprotective potential of two hybrid molecules of donepezil-tacrine in the SH-SY5Y model. Cytotoxicity and hepatotoxicity assays were performed on treated cells that were collected at different times (24, 48, 72 and 120 h) in SH-SY5Y and HepG2 cell lines, respectively. Neuronal differentiation assays (morphological analysis), protein expression, cell cycle kinetics, cell proliferation, mitochondrial changes and oxidative stress were performed on SH-SY5Y cell line. Further, viability and cell death assays were performed to evaluate the neuroprotection ability of the novel hybrid compounds in SH-SY5Y cells. The compounds did not present cytotoxic effects and did not alter cell viability at the following concentrations: TA8Amino 0.0035 to 0.112?M and TAHB3 0.088 to 2.84?M; in the hepatotoxicity assays, TAHB3 reduced cell viability only at the highest concentration (2.84 ?M) and at the time of 24 h. Both hybrid compounds were able to induce neuronal differentiation and neuritogenesis, around 55% after TA8Amino and 43% after TAHB3 treatment. Only TA8Amino induced approximately 75% increase in ?-III-Tubulin expression, compatible with the formation of mature neurons. None of the treatments performed caused significant changes in cell cycle kinetics. The synthetic hybrid TA8Amino induced the production of intracellular (48.27%) and mitochondrial ROS (67.60%). Both hybrid compounds increased SOD1 expression, which could be related to the increase of oxidative damage. However, both TA8amino and TAHB3 did not promote changes in mitochondrial membrane and mitochondrial mass potential. This data demonstrate that oxidative stress induced by TA8Amino did not generate damage due to mitochondrial dysfunction in differentiated cells. In the evaluation of changes in PTEN(Ser380/ Thr382/383), AKT(Ser473) and COX2 protein expression, both hybrid compounds were able to induce PTEN and AKT expression. TA8Amino and TAHB3 promoted an increase in COX2expression indicating a possible role in the PI3K/AKT/COX2 pathway, which is related to neuronal differentiation. In the cell viability assays, TA8amino and TAHB3 showed a neuroprotective effect against the neurotoxic damage induced by the A? peptide (1-42), promoting a protection of 91.93% for TA8Amino and 54.68% for TAHB3, although the same effect could not be observed in cells treated with hydrogen peroxide. However, the induction of apoptosis by the hybrid molecules in cells treated with the A?(1-42) peptide was only slightly altered by the compounds, with a reduction of 5.10 and 4.85%, respectively, for TA8Amino and TAHB3, respectively. In general, the results of the present work demonstrate that donepezil-tacrine hybrid compounds (TA8amino e TAHB3), AChE inhibitors, have advantages as potential drugs, since they are not cytotoxic at concentration levels that inhibit AChE enzyme, besides being able to induce neuronal differentiation, neuritogenesis and neuroprotection, unlike the drugs donepezil and tacrine, tested alone.

Orientador: Man Chin Chung / Resumo: A doença de Alzheimer (DA) é a principal e mais comum causa de demência senil, contribuindo com 50-75% dos casos diagnosticados. Nos países desenvolvidos, a DA é quarta causa de morte, ficando atrás somente de doenças cardiovasculares, câncer e acidente vascular cerebral. A projeção da Organização Mundial de Saúde (OMS) é que até 2050 o número de idosos aumente 21% no mundo. A DA é uma doença neurodegenerativa progressiva, na qual os pacientes diagnosticados mostram uma extensa perda de sinapses e neurônios no hipocampo e nos córtex frontal e temporal, comprometendo de forma gradual suas funções cognitivas, como a memória, capacidade de aprendizado, raciocínio, assim como o comprometimento da comunicação e habilidade realização de atividades diárias. Atualmente não há tratamento capaz de curar ou modificar de maneira eficaz a doença, apenas medicamentos (donepezila, rivastigmina, galantamina e memantina) que melhoram alguns sintomas manifestados pelos pacientes. A redução do processo de neuroinflamação e estresse oxidativo associados ao envelhecimento e aos marcadores da DA, como a formação de placas senis e emaranhados neurofibrilares, contribui na plasticidade sináptica, cognição e memória e atenuando os efeitos associados à perda de neurônios dos pacientes acometidos pela DA. Neste trabalho foram planejados e obtidos oito compostos intermediários e nove compostos finais inéditos, planejados através da estratégia de hibridização molecular do ácido lipóico ou ácido ferúlico ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Alzheimer's disease (AD) is the main and most common cause of senile dementia, accounting for 50-75% of diagnosed cases. In developed countries, AD is the fourth leading cause of death, leading only to cardiovascular disease, cancer and stroke. The projection of the World Health Organization (WHO) is that by 2050 the number of elderly people increase by 21% in the world. AD is a progressive neurodegenerative disease, in which the diagnosed patients show an extensive loss of synapses and neurons in the hippocampus and in the frontal and temporal cortex, gradually impairing their cognitive functions, such as memory, learning ability, reasoning, and communication impairment and ability to perform daily activities. Currently there is no treatment capable of curing or effectively modifying the disease, only medications (tacrine, donepezil, rivastigmine, galantamine and memantine) that improve some of the symptoms manifested by the patients. The reduction of neuroinflammation and oxidative stress associated with aging and AD markers, such as the formation of senile plaques and neurofibrillary tangles, contribute to synaptic plasticity, cognition and memory and attenuate the effects associated with the loss of neurons in patients with AD. In this work, eight intermediate compounds and nine unpublished final compounds were obtained through the molecular hybridization strategy of lipoic acid or ferulic acid with phthalimide derivatives. All compounds were chemically characterized by 1... (Complete abstract click electronic access below) / Doutor

Student Number: 8402734 Master of Arts (Speech Pathology) Faculty of Humanities / Comprehension was assessed under various conditions in nine subjects with probable Alzheimer’s Disease. Four linguistic variables were selected, namely syntactic complexity, the use of pronouns, directness and literality. Each variable was assessed in sentences in a simple form and in a complex form. Discourse passages which included all of the variables were then constructed, and these tasks were also administered in simple and complex forms. All subjects performed qualitatively and quantitatively better under the simple conditions than under the complex for all four of the variables assessed. However, this effect was more marked in the sentence tasks than in the discourse tasks. Furthermore, individual subjects responded differently to the manipulation of the variables. Results of the study suggest that modifying the variables investigated can improve the comprehension of people with moderate to severe Alzheimer’s Disease. This has important implications for the training of caregivers and conversational partners, and suggests that this type of indirect intervention may be an effective way for speech therapists to provide clinical services to people with dementia in South Africa.

Alzheimers sjukdom, AD, är en progressiv neurodegenerativ sjukdom som orsakas av amyloida-beta plack (Ab) och nervtrådsnystan bestående av proteinet tau. Karakteristiskt för AD är förlusten av kolinerga nervceller i hippocampus och frontala cortex, som orsakar en försämring av korttidsminne och nedsatt kognitiv förmåga. Konventionella behandlingar med acetylkolinesterashämmare och NMDA-receptorantagonister har inte visat tillräcklig kognitiv effekt och behovet av behandling är stort. Syftet med denna litteraturstudie var att undersöka kognitiv effekt och säkerhet av behandling med monoklonala antikroppar vid Alzheimers sjukdom. Antikropparna som studerades var bapineuzumab, solanezumab, gantenerumab, crenezumab och ponezumab, riktade mot epitoper på Ab, och BAN2401, riktad mot protofibriller. Samtliga antikroppar var av typen humaniserad eller human tillhörande G-klassen och undersöktes i fas II-III, randomiserade, dubbelblinda och placebokontrollerade studier på patienter med mild till måttlig AD. Undantaget är gantenerumab som studerades på patienter med prodromal AD. Studier av antikropparna i transgena möss har visat förändring av Ab och en viss effekt på minne, därav togs studierna vidare. Primära utfallsvariabler var Alzheimer’s Disease Assessment Scale- Cognitive Subscale (ADAS-Cog), Disability Assessment For Dementia (DAD), The Clinical Dementia Rating – Sum of Boxes (CDR-SB) och Mini Mental State Examination (MMSE). Resultat för bapineuzumab, gantenerumab, crenezumab och ponezumab visade ingen signifikant kognitiv effekt mellan studiestart och studieslut jämfört med placebo. För solanezumab observerades en statistiskt signifikant skillnad i ADAS-Cog (p = 0,04) och MMSE (p = 0,01) jämfört med placebo, dock var skillnaderna små. ADAS-Cog, -1,6 poäng med 95% konfidensintervall -3,1 till 0,1. MMSE, 0,8 poäng med 95 % konfidensintervall 0,2 till 1,4. För BAN2401 påvisades signifikant kognitiv effekt och den har tagits vidare för en fas III-studie. Samtliga antikroppar ansågs vara säkra för patienterna med avsikt på biverkningar, dock var risken för amyloid-related imaging abnormalities (ARIA) hög vid behandling med bapineuzumab och gantenerumab. Ett läkemedel mot denna förödande folkhälsosjukdom skulle innebära ett revolutionerande framsteg för människan, sjukvården och samhället. / Alzheimer’s disease, AD, is a progressive neurodegenerative disease caused by amyloid-beta plaques (Ab) and neurofibrillary tangles composed of tau. Characteristic of AD is a loss of cholinergic neurons located in hippocampus and frontal cortex, which results in impaired short-term-memory and cognitive function. The conventional therapies, acetyl-choline-esterase-inhibitors and NMDA-receptor-antagonists, have insufficient effects and the need for a new therapy is huge. The aim of this literature study was to examinee cognitive effect and safety of therapy with monoclonal antibodies against AD. The analysed antibodies were bapineuzumab, solanezumab, gantenerumab, crenezumab and ponezumab, which are directed against epitopes of Ab, and BAN2401, which is directed against protofibrils. All antibodies were humanized or human of G-class and were examined in phase II – III, randomized, double-blind and placebo-controlled studies in patients with mild to moderate AD. The exception is gantenerumab which was studied in patients with prodromal AD. Previous studies of the antibodies in transgenic mice have shown a change in Ab and some effect on memory, hence the studies were taken to humans.  Primary endpoints were Alzheimer’s Disease Assessment Scale- Cognitive Subscale (ADAS-Cog), Disability Assessment For Dementia (DAD), The Clinical Dementia Rating – Sum of Boxes (CDR-SB) and Mini Mental State Examination (MMSE). Results for bapineuzumab, gantenerumab, crenezumab and ponezumab showed no significant cognitive effect between the start and the end of the studies, compared to placebo. There was a statistically significant difference in ADAS-Cog (p = 0,04) and MMSE (p = 0,01) between solanezumab and placebo, though the differences were small. ADAS-Cog, -1,6 points, with 95% confidence interval of -3,1 to 0,1. MMSE, 0,8 points, with 95% confidence interval of 0,2 to 1,4. BAN2401, with protofibrils as drug target, was the only antibody in which a significant cognitive effect was demonstrated. The study has been taken further to phase III. All antibodies were considered safe for patients with the intentions of adverse effects. However, the risk for amyloid-related imaging abnormalities (ARIA) was high in treatment with bapineuzumab and gantenerumab. A drug against this devastating public health disease would mean a revolutionary advance for humans, health care and the society.

The eukaryotic stress response involves translational suppression of non-housekeeping proteins, and the sequestration of unnecessary mRNA transcripts into stress granules (SGs). This process is dependent on mRNA binding proteins (RBPs), such as T- cell intracellular antigen (TIA-1). RBPs interact with unnecessary mRNA transcripts through prion and poly-glutamine like domains, and their aggregation mirrors proteins linked to neurodegenerative diseases. Recent advances in molecular genetics emphasize the importance of SG biology in disease by associating multiple RBPs linked to SGs with neurodegenerative disease. The major difference between SG proteins and aggregation prone proteins in neurodegeneration is that aggregation of SGs is transient and rapidly reverses when the stress is removed. In contrast, aggregates associated with disease are stable and accumulate over time. This study identifies overabundant SGs as a novel pathology in Alzheimer's disease and related tauopathies. The data suggest that TIA-1 is intimately linked to tau pathogenesis, acting as a modifier of tau aggregation and associated toxicity. TIA-1 is present in a protein complex with tau protein including hyper-phosphorylated and misfolded tau. The expression of WT or P301L mutant tau increases the formation and size of TIA-1 positive SGs, and the localization and dynamics of these SGs are altered. Conversely, the expression of TIA-1 increases the formation and stabilization of phospho- and misfolded tau inclusions, as well as visible alterations in microtubule morphology, perhaps reflecting a loss of tau function. The data further show that co-expression of TIA-1 and tau leads to dendrite shortening, increases in caspase cleavage, and apoptosis in primary neurons, suggesting that an interaction between TIA-1 and tau results in neurotoxicity. This toxicity is SG-dependent and is rescued by microtubule stabilizing drugs. The results of this thesis research suggest that the aggregation of tau may proceed through the SG pathway, with SG formation accelerating the pathophysiology of tau aggregation. These studies propose that these tau aggregates serve as a nidus for further accelerated aggregation of SGs, leading to formation of long-lived pathological SG.

This study aimed to understand the differences in strength or coordination of brain regions involved in processing faces in the presence of aging and/or progressing neuropathology (Alzheimer's disease). To this end, Experiment 1 evaluated age-related differences in basic face processing and the effects of familiarity in face processing. Overall, face processing in younger (22-35yrs) and older participants (63-83yrs) recruited a broadly distributed network of brain activity, but the distribution of activity varied depending on the age of the individual. The younger population utilized regions of the occipitotemporal, medial frontal and posterior parietal cortices while the older population recruited a concentrated occipitotemporal network. The younger participants were also sensitive to the type of face presented, as Novel faces were associated with greater mean BOLD activity than either the Famous or Relatives faces. Interestingly, Relatives faces were associated with greater mean B OLD activity in more regions of the brain than found in any other analysis in Exp. 1, spanning the inferior frontal, medial temporal and inferior parietal cortices. In contrast, the older adults were not sensitive to the type of face presented, which could reflect a difference in cognitive strategies used by the older population when presented with this type of face stimuli. Experiment 2 evaluated face processing, familiarity in face processing and also emphasized the interactive roles autobiographical processing and memory recency play in processing familiar faces in mature adults (MA; 45-55yrs), older adults (OA; 70-92yrs) and patients suffering from Alzheimer's disease (AD; 70-92yrs). / MA participants had greater mean BOLD activity values in more regions of the brain than observed in either of the older adult populations, spanning regions of the medial frontal, medial temporal, inferior parietal and occipital cortices. OA, in contrast, utilized a concentrated frontal and medial temporal network and AD participants had the greatest deficit in BOLD activity overall.Age-related differences in processing faces, in processing the type of face presented, in autobiographical information processing and in processing the recency of a memory were noted, as well as differences due to the deleterious effects of AD. / by Jeanna Winchester. / Thesis (Ph.D.)--Florida Atlantic University, 2009. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2009. Mode of access: World Wide Web.