Indiana University-Purdue University Indianapolis (IUPUI) / Cerebral amyloid angiopathy (CAA) is characterized by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not fully understood. In this dissertation, there are three main chapters. The first chapter investigates existing evidence regarding the amyloid diversity in CAA and its relation to tau pathology and immune response, as well as the possible contribution of molecular and cellular mechanisms, previously associated with parenchymal amyloid in Alzheimer disease (AD) and AD-related dementias, to the pathogenesis of CAA. The second chapter demonstrates differential glial reactivity and activation associated with early-stage CAA in a mouse model of Familial Danish Dementia (FDD), a neurodegenerative disease characterized by vascular accumulation of Danish amyloid (ADan). We show that early-stage CAA is associated with dysregulation in immune response networks and lipid processing, severe astrogliosis with a neurotoxic A1-astrocytic phenotype, characterized by increased expression of Complement Component 3 (C3), and decreased levels of Triggering Receptor Expressed On Myeloid Cells 2 (Trem2) with no significant reactive microgliosis. Our results also indicate how cholesterol accumulation and Apolipoprotein E (ApoE) are associated with vascular amyloid deposits at the early stages of pathology. Furthermore, we demonstrate A1 astrocytic mediation of Trem2 and microglia homeostasis. In the final chapter, we addressed whether inflammatory stimulus of other cell types are capable of inducing a subtype of neurotoxic astrocytes. Here we show a subtype of C3+ neurotoxic astrocyte are induced by activated endothelial cells that is distinct from astrocytes classically activated by microglia. We show that endothelial activated astrocytes have upregulated expression of A1-astrocytic genes and exhibit a distinctive extracellular matrix remodeling profile. Finally, we demonstrate that endothelial activated astrocytes are Decorin-positive and are associated to vascular amyloid deposits but not parenchymal amyloid plaques in mouse models and AD/CAA patients. These findings show the existence of potentially extensive and subtle functional diversity of C3+-reactive astrocytes.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20619号 / 医博第4268号 / 新制||医||1023(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 宮本 享, 教授 渡邉 大, 教授 松原 和夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 142 pages. Includes vita. Includes bibliographical references.

Dissertation (Ph.D.)--University of South Florida, 2007. / Includes vita. Includes bibliographical references (leaves 128-139). Also available online.

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La maladie d'Alzheimer (MA) et l'angiopathie amyloïde cérébrale (AAC) sont respectivement caractérisées par des dépôts de peptides amyloïdes β (Aβ) dans le cerveau et la vascularisation cérébrale. Étant donné qu’un régime riche en DHA est associé à une réduction du risque de la MA, l'objectif principal de ma thèse a été d'évaluer l'impact d'un régime enrichi en DHA sur l'inflammation systémique et ses conséquences sur les dépôts Aβ parenchymateux et vasculaires au cours du vieillissement dans un modèle de souris transgéniques de MA/AAC, les Tg2576. Les dépôts amyloïdes ont été détectés en utilisant un anticorps anti-Aβ et les hémorragies avec du bleu prussien sur des coupes cérébrales. A 10, 14 et 18 mois, nous avons démontré une réduction des dépôts vasculaires amyloïdes et des hémorragies en régime DHA par rapport au régime placebo, alors que les dépôts parenchymateux ne sont pas affectés. De plus, nous avons démontré une forte corrélation entre les dépôts amyloïdes vasculaires, les hémorragies et un médiateur pro-inflammatoire lipidique, le 12-HETE. Nous avons ensuite évalué in vitro les effets du peptide Aβ1-40 sur la production de 12-HETE par les cellules musculaires lisses vasculaires. Nous avons démontré que les niveaux d'ARNm de l'enzyme 12-LOX, impliquée dans la synthèse de 12-HETE, était augmenté lorsque les cellules ont été incubées avec du peptide Aβ1-40, suggérant une relation de cause à effet entre les dépôts Aβ et les lipides pro-inflammatoires. Mon travail a de nouveau souligné l'importance de l'inflammation dans la pathogenèse de l'AAC tout en ouvrant une nouvelle voie pour des cibles potentielles dans l'intervention préventive de cette pathologie. / Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) are characterized by Amyloid β-peptides depositions in the brain and cerebral vasculature respectively. Because DHA-diet is associated with a reduced risk of AD, the main objective of my thesis was to evaluate the impact of a DHA-diet on cerebrovascular and peripheral inflammation and its consequences on parenchymal and vascular Aβ-deposits during aging in a transgenic mouse model of AD/CAA (Tg2576). The Aβ-peptide deposits were detected using an anti-Aβ peptides and hemorrhages were detected with Prussian Blue on brain sections. At 10, 14 and 18 month-old, we demonstrated a reduction of amyloid vascular deposits and hemorrhages under DHA-diet compared to placebo, while parenchymal Aβ-peptides deposits remain unaffected. Moreover, we demonstrated a strong negative correlation between amyloid vascular deposition, hemorrhage and a lipid-derived pro-inflammatory mediator, 12-HETE. We next evaluated the in vitro effects of Aβ1-40-peptide on 12-HETE production by the Vascular Smooth Muscle Cells. We demonstrated that the mRNA level of the 12-LOX enzyme, involved in 12-HETE synthesis, was increased when cells where incubated with Aβ1-40-peptide, suggesting a cause-to-effect relationship between Aβ deposits and pro-inflammatory biolipids. The work carried out during my thesis made it possible to demonstrate DHA protective effect on evolution and consequences of Aβ peptide cerebrovascular accumulation and link it to plasma 12-HETE level. My work emphasized once again the importance of inflammation in AAC pathogenesis while opening up a new pathway for potential targets in the preventive intervention of this pathology.

Contexte : Les hémorragies intracérébrales spontanées (HIC) sont grevées d’une mortalité élevée et d’un pronostic fonctionnel sombre. Les données concernant le pronostic à long terme des HIC sont rares. L’objectif principal de ce travail était d’étudier le pronostic au long cours des HIC en les abordant par le prisme de leur histoire naturelle.Méthodes : Nos populations d’étude sont issues de la cohorte prospective PITCH (Prognosis of IntraCerebral Haemorrhage) qui est une cohorte observationnelle ayant inclus de façon consécutive tous les patients admis au CHU de Lille pour une HIC spontanée entre 2004 et 2009. Nous avons étudié (i) l’incidence de la démence de novo post HIC ainsi que les facteurs prédictifs cliniques et neuroradiologiques associés à sa survenue ; (ii) la prévalence de la sidérose superficielle corticale (SSc) et les facteurs cliniques et radiologiques associés ; (iii) les facteurs prédictifs de récidive hémorragiques.Résultats : Nous avons mis en évidence qu’il existait un risque majeur de démence de novo chez les patients survivant à une HIC. Les facteurs prédictifs de démence identifiés tels que la localisation lobaire ou la SSc suggèrent une implication directe de l’angiopathie amyloïde cérébrale. Nous avons également montré qu’au sein de notre cohorte, un patient sur cinq avait de la SSc sur l’IRM cérébrale réalisée à l’admission. La SSc apparaissait être un facteur neuroradiologique prédictif majeur de récidive hémorragique.Conclusion : Les résultats de ce travail ont un impact important dans la prise en charge des patients ayant eu une HIC spontanée et permettront d’informer de façon adéquate les patients et leurs aidants. Ils apportent des informations nouvelles sur l’évaluation du risque de récidive hémorragique et sur d’éventuelles futures cibles thérapeutiques. / Background: The low frequency of spontaneous intracerebral haemorrhage (ICH) and its high mortality rate may explain the paucity of data in long term outcomes. The main objective was to study long term prognosis of ICH through the prism of their natural history.Methods: Our study populations were based on the PITCH (Prognosis of IntraCerebral Haemorrhage) cohort which is an observational study that included consecutively adults admitted at the Lille University Hospital for spontaneous ICH between 2004 and 2009. We aimed to determine (i) the incidence of new onset dementia and its clinical and radiological predictive factors; (ii) the prevalence of cortical superficial siderosis (cSS) and its associated factors; (iii) predictive factors of recurrent ICH.Results: We showed that the risk of new onset dementia is substantial after spontaneous ICH. Predictive factors of new onset dementia such as ICH lobar location and cSS suggest the implication of underlying cerebral amyloid angiopathy. We found that one out of five patients had cSS on baseline MRI. cSS was a strong predictive factor of recurrent ICH. Conclusion: These findings are of immediate clinical relevance in the management of ICH patients and will allow to adequately inform patients and caregivers. These results may provide additional information on ICH recurrence risk assessment and may contribute to the development of future therapeutic strategies.

Introduction: Alzheimer's disease is a neurodegenerative disease that initially manifests itself primarily as impaired short-term memory and impaired language ability. The course of the disease is mainly due to an atrophy in the brain that can be attributed to the protein amyloid B and tau. Monoclonal antibodies that target Alzheimer's disease often have a high rate of cerebral edema, where proteinaceous fluid leaks into the extracellular space of the brain and creates edema. Some of the most common symptoms for amyloid-related imaging abnormalities (ARIA-E) are headache, dizziness, and blurred vision. In a few cases, patients with ARIA-E need to be hospitalized for observation, but most show a decline in ARIA-E within one to two months. Objective: To investigate the frequency of ARIA-E in clinical studies of monoclonal antibodies to patients with Alzhiemer's disease and to investigate the role of the ApoE4 allele in the development of ARIA-E. Method: Literature review of five RCT studies based on four different monoclonal antibodies. PubMed was used to search for the RCT-studies. Results: ARIA-E varies between different types of antibodies. ARIA-E usually occurs early in treatment when the degree of amyloid b is highest in the brain. Most cases are asymptomatic and treatment resumes within 1-2 months. Conclusion: Aria-E frequency correlates strongly with dose strength as well as APOE4 -status and most of the incidences are asymptomatic. With the right titration and individually selected drugs as well as individual dosages a safe care can be established for patients with Alzheimer's disease. If treatment is initiated at an early stage, the risk of side effects is reduced and more neurons can be saved from atrophy. The combination of several different types of medicine will further reduce the risk of ARIA-E.

En aquest treball de tesis doctoral s'estudia el paper de l'estrès oxidatiu tant a la etiologia com a la patofisiologia del dany vascular associat a la malaltia d'Alzheimer. Es demostra la capacitat de les cèl·lules musculars llises vasculars de produir pèptid β-amiloide (Aβ). L'estrès oxidatiu associat a edats avançades, estimula el processament amiloidogènic de l' APP a cèl·lules musculars llises vasculars portant a un augment de producció d' Aβ1-40 i Aβ1-42 contribuint així, a la formació dels depòsits amiloides vasculars. Alhora, els depòsits amiloides vasculars indueixen dany vascular a través d'estrès oxidatiu, a on la nitrotirosinació de proteïnes juga un paper clau en la inactivació d'enzimes essencials per la viabilitat cel·lular. La vitamina E i els estrogens tenen un efecte protector a neurones i cèl·lules musculars llises vasculars mentre que la vitamina E, però no els estrogens, és capaç de protegir les cèl·lules endotelials davant la toxicitat induïda pel pèptid Aβ. / In this thesis we study the effect of oxidative stress in the etiology and pathophysiology of the vascular damage associated to Alzheimer's disease. We demonstrate the production of amyloid-β-peptide (Aβ) by vascular smooth muscle cells. Oxidative stress related to advance ages, induces the amyloidogenic APP cleavage producing an increase of Aβ1-40 and Aβ1-42 by vascular smooth muscle cells, which in tum contribute to vascular amyloid deposits generation. Vascular amyloid deposits induce oxidative stress, in which protein nitrotyrosination plays a key role in essential enzymes inactivation. Vitamin E and estrogens are able to protect neurons and vascular smooth muscle cells while vitamin E, but not estrogens, is able to protect endothelial cells against Aβ-mediated toxicity.