Mancini 2017 Thesis

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Mancini G (2017) Colesterol dietético e doença de Alzheimer em modelos experimentais: avaliação da resposta sináptica, mitocondrial e comportamental. Doctoral Thesis p118.

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Mancini G (2018) Doctoral Thesis

Abstract: Cholesterol is a vital component of the human body. This compound has peculiar characteristics that give it several physiological functions, such as a component of the plasma membranes, as a precursor of steroid hormones, bile salts and vitamin D, moreover, as a key role in mechanisms of learning and memory, such as synaptic plasticity. Hypercholesterolemia (HC) is a human's condition which the subjects display a high plasma cholesterol levels. This status is characterized by deregulation of cholesterol homeostasis, therefore, has been considered the main risk factor for the development and progression of atherosclerosis, and it's the leading cause of death from cardiovascular diseases (CVD). Studies shown that HC induces vascular impairment, and this vascular dysfunction may to cause cerebrovascular diseases, such as vascular dementia. Alzheimer's disease (AD) is a multifactorial disease that affects both the central nervous system (CNS) and peripheral system. Individuals with AD exhibit severe memory impairment and other cognitive impairments. However, the causes of AD development are still unknown. The vascular hypothesis for AD postulates that the reduction of the cerebral blood flow (CBF), due to a neurovascular uncoupling, for example, would be the initial event of the neurodegeneration processes. Reinforcing this hypothesis, risk factors associated with vascular diseases, as hypercholesterolemia, are involved in the development and progression of AD. In this sense, the hypothesis of this work is that cognitive, synaptic and neurovascular damages observed in AD, would be exacerbated by hypercholesterolemia induced by a high cholesterol diet. To this end, we fed for 8 weeks a triple transgenic mouse (3xTg-AD) and non-transgenic mice (NTg), of both sexes, with a diet enriched in fat/cholesterol (HFCD). Herein, our results show that the ingestion of HFCD induced hypercholesterolemia in both genotypes without body weight gain. In addition, HFCD induced spatial and recognition memory impairment in NTg mice similar to 3xTg-DA mice. NTg HFCD-fed displayed changes in exploratory and aversive behavior, and exhibited increase in locomotion. 3xTg-AD mice did not display an intensification on HFCD-induced cognitive impairments, already observed in this model. Next, we seek to elucidate the mechanisms by which HFCD induces cognitive impairments in NTg mice. The ingestion of HFCD induced a decrease in the •NO bioavailability and a decrease in the rate of mitochondrial O2 consumption in hippocampal slices of both genotypes. Finally, we observed that the HFCD induces an impairment in BBB altering components as aquaporin-4 (AQP-4) in NTg mice and tomato lectin in 3xTg-DA mice. Together, the results of the present study reinforce the vascular hypothesis for the development of AD. Thus, these data encourage studies on modifiable risk factors, in other words, an improvement in life habits, especially in food intake, for individuals without genetic predisposition may bring benefits that resulted in a better quality of life during the advancement of the age.

Keywords: Colesterol, Hipercolesterolemia, Doença de Alzheimer, 3xTg-DA, Hipocampo, Acoplamento neurovascular, BHE, Óxido nítrico, Consumo de O2 mitocondrial Bioblast editor: Kandolf G, Garcia-Souza LF O2k-Network Lab: BR Florianopolis Fabro de Bem A

Labels: MiParea: Respiration, Exercise physiology;nutrition;life style  Pathology: Aging;senescence, Alzheimer's, Cardiovascular 

Organism: Mouse  Tissue;cell: Nervous system  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k 

Labels, 2018-03