Investigating Pathogenic Mechanisms and Biomarkers in Alzheimer’s Disease

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Araujo Goncalves da Silva, Rafaella
Alzheimer’s disease (AD) is the most common form of dementia among the elderly and a major public health issue worldwide. Despite decades of research efforts, AD still lacks an effective treatment. Although the first two histopathological markers of AD identified in the 1980’s are brain deposits of extracellular amyloid β (Aβ) and intraneuronal tau, more recently, other pathways have been implicated in disease pathophysiology. Modifiable risk factors associated with lifestyle interventions, including diabetes, depression and sedentarism, are linked to AD, and the identification of shared molecular mechanisms between these risk factors and dementia has the potential to contribute to elucidate disease etiology. A big obstacle in developing therapeutics for AD is the difficulty in diagnosing this disease before substantial neuronal loss and cognitive impairment. In this context, blood has emerged as a promising cost-effective and less invasive source of disease biomarkers in patients. This thesis aims to investigate pathogenic mechanisms associated with AD, including inflammation, metabolic dysfunction, and impaired hormonal signalling, and to propose a novel approach to measure in vivo biomarkers in blood samples from neurodegenerative disease patients. More specifically, findings presented in this thesis indicate a role for pro-inflammatory interleukin-6 (IL-6) and tau pathology in mediating metabolic and cognitive alterations in AD mice; propose a novel shared molecular signature between depression and dementia involving reduced cerebrospinal fluid (CSF) levels of the exercise-induced hormone irisin and the pro-resolving and anti-inflammatory mediator lipoxin A4; describe an approach to identify biomarkers of neurodegeneration from patients’ blood samples using neuronal-derived extracellular vesicles (NDEVs) purified using the synaptic marker synaptosomal-associated protein 25 (SNAP25). Overall, these results are relevant to our understanding of AD pathogenic mechanisms and disease biomarkers.
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