Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's disease

• Autor(a) principal: Morgado, Bárbara Marcos
• Data de Publicação: 2018
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/25073
• topic: Dementia; Alzheimer’s Disease; Type 2 Diabetes Mellitus; Metformin; Attention-deficit/hyperactivity disorder; APP (Alzheimer’s precursor protein); Tau

Alzheimer’s disease (AD) and Type 2 Diabetes Mellitus (T2DM) are respectively characterized as a neurodegenerative disorder and a peripheral metabolic. Evidence strongly suggests an association between these two diseases, where T2DM is starting to be considered as a risk factor for AD. Both diseases share many pathophysiological features, including insulin resistance, amyloid type aggregation and oxidative stress. The anti-diabetic drug metformin was shown to affect APP metabolism and Aβ generation, through AMPK-dependent mechanism. There are however conflicting reports, where metformin is considered to provide neuroprotection or conversely increase the risk of AD; the clinical significance of metformin action on AD pathology remains to be clarified. This work aims to contribute towards clarifying the molecular mechanism underlying the effects of metformin on AD patients. Using patient-derived human dermal fibroblast cultures as an experimental model, metformin was shown to supress APP cleavage resulting in intracellular protein accumulation. Moreover, the drug decreased MAPT and β-Actin gene expression levels. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder most commonly affecting children and teens. It was fist associated to dementia in 2011, where adults diagnosed with dementia revealed an increased prevalence of prior childhood ADHD symptoms. The present study is pioneer regarding the molecular association between both diseases, investigating whether adult ADHD may precede AD long before its clinical onset.