Cortical alterations of peptidergic secretion in Alzheimer's disease = Alteraciones corticales de la secreción peptidérgica en la enfermedad de Alzheimer

[eng] The Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by neurological alterations that lead to a severe cognitive decline and dementia. Nowadays has become the main cause of dementia, accounting for 50–70% of cases (Winblad et al., 2016). Commonly, the first symptom of the dementia is the difficulty in the recall of recent events, which can progress rapidly into different personality and behavioral changes and a more severe impairment of the memory. Progressive advance of cognitive impairment interferes in the development of daily activities, causing a high grade of dependence, mainly in the final phases of the disease. (Winblad et al., 2016). As the prevalence of overall dementia rises steeply with age, being this factor the strongest risk factor for AD (American Psychiatric Association, 2013), the progressive aging of the population is increasing the incidence of the disease, which has become a global health problem. In fact, an estimated 40 million people, mostly older than 60 years, have dementia worldwide, and this number is estimated to double every 20 years, until at least 2050 (Qiu et al., 2009). This insidious onset and the gradual progression of impairment of AD –the average duration of illness is 8–10 years (Masters et al., 2015)- makes this pathology specially harmful compared to other diseases with a more clear clinical onset, and often abrupt resolution (Jack, 2012). Because of that, the disease has become an important economic charge for the health systems, which have to take care of a rising number of highly dependent people.[spa] The Alzheimer’s disease is a disorder characterized by the presence of senile plaques and neurofibrillary tangles caused by the aberrant accumulation of β-amyloid peptide and hyperphosphorylated Tau, respectively. Nowadays, AD is the main cause of dementia, being aging its main risk factor. Given that progressive alterations have been detected in neuropeptide levels in patients and animal models of Alzheimer's disease, it has been suggested that this pathway may be involved in the neurophysiology of the disease. In this doctoral thesis, we study the cortical alterations of the peptidergic secretion pathway in Alzheimer's disease. During its elaboration, the localization of dense granule proteins in the normal brain has been characterized and aberrant accumulations of these are found in the pathological structures typical of the disease, such as granulovacuolar degeneration bodies or dystrophic neurites. The study of the acute effect of β-amyloid peptide showed a reduction of the regulated peptidergic release in neurons and astrocytes in vitro as well as in acute brain slices in response to the treatment, suggesting that the secretion pathway can suppose an early target of the pathology. Finally, the content analysis of characteristic proteins of the pathway showed a reduction of their levels in the cerebrospinal fluid of transgenic animals and patients with mild cognitive impairment, which may suggest that the proteins of the route can be candidates as progression biomarkers to monitoring of the progression of Alzheimer's disease