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Beyond the canonical model of amyloid cascade – a complex network of the regulatory mechanisms implicated in brain aging and Alzheimer’s disease

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Defense Thèse de privat-docent : Univ. Genève, 2017
Abstract This thesis describes the complex network of regulatory mechanisms implicated in brain aging and Alzheimer’s disease (AD). Specifically, it focuses on those regulatory mechanisms that, whilst not being traditionally attributed to amyloid cascade, may still be critical for the determination of individual cognitive trajectories upon aging. The thesis consists of four articles which are preceded by a short introduction and succeeded by a section of concluding remarks. The first article presents the conceptual framework of AD. It describes the evolution of the AD model over time and discusses the role of different compensatory mechanisms in the pathogenesis of AD. Notably, the strengths and limitations of Jack’s dynamic AD model are discussed in detail. Articles 2 to 4 offer some examples of regulatory mechanisms that, acting beyond amyloid cascade, affect brain aging and which therefore may be relevant to AD. Namely, they reveal the role of inflammatory regulators (article 2) and genetic background (articles 3 and 4) in the progression of neurodegeneration process. Specifically, article 2 concerns the role of major histocompatibility complex I (MHCI) in the maintenance of synaptic integrity upon aging while articles 3 and 4 refer to so called ‘tau-negative’ or ‘plaquepredominant’ AD and discuss the possible implication of chorein and GNA14 genes in the pathogenesis of this rare form of dementia.
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LAZARCZYK, Maciej. Beyond the canonical model of amyloid cascade – a complex network of the regulatory mechanisms implicated in brain aging and Alzheimer’s disease. Université de Genève. Thèse de privat-docent, 2017. https://archive-ouverte.unige.ch/unige:100346

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Deposited on : 2017-12-14

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