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Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN
Contributor:Wojda, Urszula (1963- ) : Supervisor ; Mietelska-Porowska, Anna : Assistant supervisor
Publisher:Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN
Place of publishing: Date issued/created: Description:167 pages : illustrations ; 30 cm ; Bibliography ; Summary in English
Degree grantor:Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN
Type of object: Subject and Keywords:Alzheimer’s disease ; Amyloid-β ; Astroglia ; Inflammation ; Metabolic syndrome ; Microglia
Abstract:
Alzheimer's disease (AD) develops silently as a pre-symptomatic stage for many years, and only after 10-20 years clinical symptoms such as memory and cognitive decline appear. There are many hypotheses regarding the causes, sequence of events and molecular mechanisms of AD development, but none of them covers the complexity of the disease etiology, what translates into the lack of effective treatments. In addition, increasing evidence indicates that modifiable environmental factors, such as an unbalanced diet or past infections, play an important role in the development of AD. In the absence of effective treatments, prevention seems to be the best way to reduce the incidence of AD. However, designing an effective preventive strategy requires a holistic understanding of the interrelationships between organs, cells, and signaling pathways linking risk factors with the AD pathology. Therefore, the aim of this study was to verify the hypothesis that an improper diet, such as the Western diet (WD), by inducing metabolic syndrome and systemic inflammation, may accelerate and/or intensify brain inflammation and neuropathological changes characteristic of AD. In the study, transgenic mice expressing the human amyloid precursor protein gene with the Swedish mutation (APPswe) were used. Mice were analyzed in 5 age groups: 4, 8, 12, 16 and 20 months, corresponding to the age ranges in humans: 25, 35, 45, 65, 75 years, respectively. The 4- to 12-month-old mice corresponded to pre-symptomatic stages where the pathological processes leading to the aggregation of Aβ peptides are taking place, while Aβ senile plaques are not yet present. In each age group, 4 experimental subgroups were tested: 1) CTR – control group, mice fed a standard diet, 2) WD – mice fed a Western diet, 3) LPS – mice fed a standard diet, which were treated with intraperitoneal administration of lipopolysaccharide (LPS) for induction of systemic inflammation, and 4) WD+LPS – WD-fed mice given LPS intraperitoneally. This study characterizes for the first time a detailed sequence of systemic and metabolic changes, followed by neuroinflammation and Aβ pathology in the hippocampus and entorhinal cortex induced by WD in APPswe mice. It has been shown that 3 weeks of feeding WD causes hypercholesterolemia and fatty changes in hepatocytes. After 5 months of WD, the induced metabolic changes were joined by obesity and non-alcoholic fatty liver disease, which indicates a developed metabolic syndrome. At the same time, an increase in the concentration of white blood cells was observed, suggesting the presence of low-grade systemic inflammation. The analysis of brain tissue showed that the hippocampus, compared to the entorhinal cortex, is a structure more sensitive to the diet composition. 3 weeks of WD accelerated by 4 months the increase in the level of APP and its C-terminal proteolytic fragments and the activation of astrocytes. After 5 months of WD, the activation of microglial cells was additionally observed to be accelerated by 4 months and its phagocytic functions disturbed, which was most likely the cause of the process of amyloid plaque deposition in the hippocampus accelerated by 8 months. Comparison of WD-induced changes with LPS-induced changes showed that WD induces stronger inflammatory response in the brain and, unlike LPS, is closely related to amyloidogenesis and not pTau(Thr231) protein phosphorylation in APPswe mice. The obtained results indicate that WD can significantly accelerate the pathology of AD, and that AD is a disorder of the whole organism, where peripheral organs may play a key role in its pathogenesis. In particular, WD-induced liver damage may affect the disturbed cholesterol metabolism and lead to impaired amyloid degradation and removal processes, which seems to be one of the main factors accelerating the development of AD. The obtained results may support the development of methods for effective prevention and early treatment of AD.
Nencki Institute of Experimental Biology of the Polish Academy of Sciences
Original in:Library of the Nencki Institute of Experimental Biology PAS
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