Estudo da associação entre doença de Alzheimer, alterações dos níveis periféricos de colesterol e resposta inflamatória relacionada ao inflamassoma NLRP3

• Ano de defesa: 2023
• Autor(a) principal: Gabriela Lopes Martins
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; ICB - DEPARTAMENTO DE FARMACOLOGIA; Programa de Pós-Graduação em Ciências Biológicas - Fisiologia e Farmacologia; UFMG
• Palavras-chave em Português: Doença de Alzheimer; Demência; Colesterol; Metabolismo lipídico; Inflamação; Inflamassoma NLRP3; Fisiologia; Inflamassomos
• Link de acesso: http://hdl.handle.net/1843/73558

Dementias are debilitating health conditions that significantly affects the elderly in Brazil and around the world, causing impacts not only on affected patients, but also on their families and caregivers. Among these, Alzheimer's disease (AD) is highlighted, as it is the most common cause of dementia among individuals. The deposition of amyloid β peptide (Aβ), together with the formation of tau protein neurofibrillary tangles, are the main mechanisms that contribute to the pathophysiology of AD. However, factors such as inflammation and dysregulation of lipids such as cholesterol, both peripheral and central, have also been associated with the disease. Therefore, the objective of this study was to evaluate associations between three factors: peripheral lipid changes; inflammatory responses; and AD. For this, the study was carried out in two parts: in an animal model and in humans. In the in vivo study, double transgenic mice for AD and controls were subjected, at six weeks of age, to a standard diet or a diet with an increase of 1.25% cholesterol for 18 weeks. From the samples collected at the end of this period, serum and hepatic lipid profiles and inflammatory mediators were measured, including molecules related to the NLRP3 inflammasome – interleukins (IL)-1β and 18, and caspase-1 – in hippocampus and prefrontal cortex samples. After comparing the results between the experimental groups, there was no difference in serum total cholesterol (TC) levels. However, in liver samples, the values of this lipid were significantly higher in animals fed the cholesterol-enriched diet, as well as the hepatosomatic index, compared to those receiving the standard diet, in both genotypes. With regard to inflammatory cytokines, animals that received the diet with added cholesterol, both transgenic and controls, showed higher levels of hippocampal IL-18, compared to those fed the standard diet. Therefore, these data demonstrated that the diet with increased cholesterol caused liver changes and neuroinflammation involving IL-18 signaling, regardless of the genotype, i.e., not associated with AD in the animal model studied. In humans, a cross-sectional study was carried out, in which clinical and demographic data were collected, anthropometric parameters were measured and blood was collected to obtain serum and plasma samples. We evaluated 23 patients diagnosed with AD, 9 with frontotemporal dementia (FTD) and 33 controls. Lipid profile and other biochemical parameters were measured, as well as inflammatory mediators, including molecules related to the NLRP3 inflammasome pathway. Results were compared between patients with AD, FTD, and controls, as well as grouped dementia patients (AD+FTD) and controls. Furthermore, multivariate logistic regression analysis was performed to assess whether any variable was independently associated with AD or the presence of dementia (AD+FTD), as well as correlations between the study variables. Although the frequency of self-reported dyslipidemia was the same between groups, patients with dementia (AD+FTD) had significantly elevated serum concentrations of low-density lipoprotein cholesterol (LDLc) compared to controls. Furthermore, in the AD+FTD and AD groups, higher plasma levels of IL-1β were observed, compared to controls, as well as other cytokines, such as IL-6, IL-8, IL-12p70, and tumor necrosis factor (TNF). Logistic regression analyses, however, did not reveal any variables independently associated with these conditions. Furthermore, in both AD+FTD and AD groups, correlations were observed between lipid profile parameters (TC and LDLc), anthropometric measurements (waist circumference and body mass index), and molecules related to the NLRP3 inflammasome (IL-18 and caspase -1). Although the results presented do not allow direct associations between the factors evaluated in the study (peripheral changes in cholesterol, NLRP3 inflammasome, and AD), it was possible to verify that there are correlations between them. Furthermore, the association between these three factors, together, had not yet been evaluated in any study. Thus, the data presented here support the development of further studies involving a larger sample size and other experimental designs, for a better understanding of the mechanisms involved among the objects of this study. This, in turn, may contribute to elucidate potential therapeutic targets for AD and dementia, which remain without a cure.