Adrenomedullin, a new therapeutic target for the treatment of Alzheimer's disease

Abstract

One of the consequences of the ageing world population is the increase in neurodegenerative diseases such as Alzheimer’s or frontotemporal dementia. Neurodegenerative diseases are pathologies characterized by a gradual and irreversible deterioration of neurons and presenting with different neurological syndromes depending on the affected brain area. Dementias are the most common neurodegenerative disorders, for which therapeutic options are very limited and merely symptomatic, rather than neuroprotective or neuroregenerative. Furthermore, the most common dementia disorders, Alzheimer’s disease or frontotemporal dementia, affect over 7 million people in Europe, and this figure is expected to double every 20 years as the population ages. The estimated care costs for dementia in Europe are approximately €130 billion per year, which cause a big concern on public health systems. Together with this, there is also an enormous social and human burden on patients as well as caregivers. For this reasons, one of the major challenges faced by neuroscience research field is to bring more insights into the molecular pathomechanisms that underlie the neurodegenerative processes in dementia disorders in order to design novel pharmacological approaches and develop successful therapies for preventing or treating dementia. The cytoskeleton plays an essential role on many fundamental neuronal processes, such as neuronal migration, cargo transport, polarity, and differentiation. Perturbations in the architecture of cytoskeleton can result in the loss of neuronal functions leading to neurodegeneration. This thesis aims to study the role of alterations in the cytoskeleton in the pathogenesis of neurodegenerative diseases. In particular, the thesis will focus on the involvement of adrenomedullin in alterations of the cytoskeleton and its relationship with two of the most common dementias, Alzheimer’s disease and frontotemporal dementia. First, an overview of the current status of adrenomedullin, with special focus on its interaction with the cytoskeleton, along with a summary of the most relevant neurodegenerative diseases and the different possible pathways by which adrenomedullin might mediate its actions will be provided in the Chapter I, Introduction. Chapter II describes the hypothesis and objectives of the present thesis. Chapter III presents a study on the involvement of adrenomedullin in Alzheimer’s disease and the purported mechanism of action by which adrenomedullin exert its effects in the course of the disease. Chapter IV describes changes in adrenomedullin expression in the ageing brain. In addition, it is described in this chapter the effects on cognition of deleting adrenomedullin gene in the CNS (AMKO mouse model) and the effects of ageing in this model. Chapter V presents a brief study on the involvement of adrenomedullin alterations on frontotemporal dementia and the possible influence on cytoskeleton. Finally, Chapter VI, General Discussion, integrates and highlights the most relevant aspects of the previous chapters, to end with the Chapter VII, Conclusions, summarising the main findings of the present thesis.