Amyloidoses are a group of protein misfolding diseases characterized by deposits of insoluble fibrillar protein aggregates. Medin amyloid, which is the focus of this thesis, appears in the media of the thoracic aorta in nearly all individuals over 50 years. The fibrils are derived from a 50 amino acid residue fragment of the precursor protein lactadherin. How medin amyloid arises is unknown, but in paper I we demonstrated, with immunohistochemical and in vitro binding experiments, that both lactadherin and medin interact with elastin, implying that the elastic fibre is central in amyloid formation. In paper II, we further showed that the last 18-19 amino acid residues constitute the amyloid-promoting region. In paper III, the consequence of medin deposition was investigated. Aortic specimens from patients with thoracic aorta aneurysm and dissection were examined for medin content. The tissue findings indicated that the two disease groups contained more medin oligomers than normal aortas. Interestingly, recent reports demonstrate that the toxicity of amyloid proteins is attributed to prefibrillar oligomeric aggregates rather than to mature fibrils. In support of this finding, we observed that prefibrillar medin, in contrast to medin fibrils, was toxic in cell culture. Amyloid formation is a nucleation-dependent process. Addition of preformed fibrils to an amyloid protein solution dramatically accelerates fibrillation, a phenomenon called seeding. In paper IV, serum amyloid A-derived (AA) amyloid was found co-localized with medin deposits in the aorta. In vitro, medin fibrils enhanced the formation of AA fibrils, indicative of a seeding mechanism. The data are of great importance as they suggest that one type of amyloid is capable of inducing fibrillation and deposition of another amyloid type. In conclusion, the results of this thesis shed light on how medin is formed, the function of lactadherin and the consequences of medin deposition for aortic pathology.

Amyloid is a form of abnormal protein aggregation within the living body. Massive deposits can lead to organ failure. There is also increasing evidence that smaller pre-amyloid aggregates exert direct toxic effects to cells. To date 25 different proteins are known to occur as amyloid deposition in human tissues, although not all of these conditions are known to be associated with clinical diseases. This thesis deals with the very common form of amyloid localized to the arterial media. The fibril protein called ‘medin’ was identified in 1999. Medin is a 50 amino acid residue internal fragment of the precursor protein lactadherin. Lactadherin, first found in human milk, is expressed in various tissues such as breast epithelium (including carcinomas), macrophages and aorta. The function of the protein is not known but it has several functional domains. There is an EFG like domain, including an RGD-sequence, in the N-terminal part of the molecule. The C-terminal part consists of C1 and C2 coagulation factor V and VIII like domains. Medin is from within the C2 domain. This region is suggested to be involved in phosphatidyl serine binding, important in phagocytosis of apoptotic cells. Medin amyloid was originally described from studies of the aorta. It is shown here that deposits are more widely spread and can be found in many large arteries, particularly within the upper part of the body. The prevalence of medin amyloid increases with age and deposits are found, to a certain degree, in virtually everyone above the age of 60 years. The amyloid is not only found extracellularly but intracellular deposits may also occur. Amyloid is usually associated with elastic lamina or lamellae which often show signs of fragmentation. Given the localization of amyloid to elastic structures of the arterial media, three different vascular diseases were studied: temporal (giant cell) arteritis, thoracic aortic aneurysm and thoracic aortic dissection. Medin amyloid was found in temporal arteries with and without inflammation. In inflamed arteries, amyloid was mainly located along the broken internal elastic lamina. Medin was also demonstrated within giant cells. It is suggested that medin may be an antigen triggering autoimmune giant cell arteritis. In the study of thoracic aortic aneurysms and dissections, we found significant less medin amyloid in diseased aortic tissues compared with a control material. On the other hand, immunoreactive medin, probably in the state of oligomeric aggregates, was regularly found in association with aneurysms and dissections but not in the control material. It is suggested that medin oligomers exert toxic effects on smooth muscle cells which may lead to weakening of the arterial wall with aneurysm or dissection as a consequence.

La compréhension du fonctionnement du corps humain est un challenge de recherche an de prendre une décision médicale (le diagnostic, le traitement) adéquate dans le cas des pathologies liées au syst ème musculosquelettique. Pour faire face à cette problématique, dans un premier temps, un modèle biomécanique a été développé décrivant la dynamique du mouvement avec prise en considération des caractéristiques géométriques (os et muscles) et mécaniques du système musculo-squelettique. Une étude de sensibilité de ces paramètres géométriques à partir des données de la littérature a montré l'importance de la personnalisation des ces paramètres. En application, un cas d'étude clinique d'un sujet présentant une pathologie (Heine-Medin (polio)) a été étudié. Deux modèles personnalisés (un sujet sain et un sujet pathologique) ont été réalisés. Les résultats obtenus ont montré l'intérêt d'une modélisation personnalisée pour évaluer et concevoir des orthèses personnalisés. Dans un deuxième temps, nous avons proposé une nouvelle classe de modèle - un méta modèle (Système d'Aide à la Décision) - intégrant des résultats du domaine de l'ingénierie des connaissances pour prédire, diagnostiquer, classer et proposer un traitement des pathologies du système musculo-squelettique des membres inférieurs (anomalies rotationnelles (AR), enfants PC (Paralysie Cérébrale), pied bot). La modélisation de ce méta modèle se base sur les modèles mathématiques prédictifs pour prendre une décision médicale (une prédiction, un diagnostic, ou une classi cation). Le but nal est de dégager un résultat cliniquement applicable. Ce système est générique, exible, et extensible et permet donc l'étude et l'analyse de pathologies diverses du système musculosquelettique des membres inférieurs. Enn, une comparaison de ces deux approches de modélisation a été eectuée an d'évaluer leur complémentarité pour une utilisation clinique.