Capucho, Adriana Margarida Mateus The role of carotid body in brain insulin resistance and neurodegeneration / Adriana Margarida Mateus Capucho ; orient. Sílvia Vilares Conde, Hugo Vicente Miranda

The role of carotid body in brain insulin resistance and neurodegeneration / Adriana Margarida Mateus Capucho ; orient. Sílvia Vilares Conde, Hugo Vicente Miranda . - Lisboa : NOVA Medical School, 2022 . - xxiv, 93 p. : il., fig. . -
Recent epidemiological studies have shown that individuals who develop Type 2 Diabetes (T2D) at an early age have an increased risk to develop neurodegenerative disorders, as Alzheimer’s (AD) and Parkinson’s Disease (PD). A common characteristic between T2D and these neurodegenerative disorders is the development of an insulin resistance state. Considering that the therapeutics that exists to neurodegenerative disorders only attenuate the symptoms and have several side effects, it is important to search for novel disease modifying therapies. Recently, Conde’s group showed that in states of insulin resistance, glucose intolerance and obesity, features associated with T2D, the carotid bodies (CBs) were overactivated. The CBs are peripheral chemoreceptors classically defined as oxygen sensors, and in the last years they havebeen described as metabolic sensors. Moreover, when CBs activity was abolished via the resection of the carotid sinus nerve (CSN), which transmits the information from the CBs to the brain, T2D dysmetabolic features were reverted. Considering that dysmetabolism is a risk factor to the development of neurodegenerative disorders, the main goal of this project was to investigate if the abolishment of CBs activity via bilateral resection of the CSN could prevent/ameliorate the neurodegenerative process, and cognitive impairment associated with brain insulin resistance. For that, we have used an animal model of dysmetabolism, the high fat-high sucrose (HFHSu) diet animal and tested the effect of the abolishment of CBs activity, through the resection of the CSN, on whole-body glucose metabolism and on the behavioural activity of the animals. Moreover, the levels of insulin signalling- related proteins, synaptic and neurodegenerative markers in prefrontal cortex and in the hippocampus were evaluated. We observed that the HFHSu animals exhibited impaired cognitive and olfactory functionsevaluated by the y-maze and the block tests. In contrast, the CSN resection prevented this phenotype in the y-maze test. Additionally, HFHSu diet led to an increase in the levels of advanced glycation end products (AGEs), and the amyloid precursor protein (APP) in the hippocampus, while the CSN resection attenuating this second effect. In the prefrontal cortex, it was observed an increase in the levels of alpha-synuclein (aSyn), and APP, effects abolished by CSN resection. In conclusion, this project demonstrate that CBs modulation might have a role in preventing neurodegenerative processes associated with insulin resistance. Neurodegenerative Disorders
Diabetes Mellitus - Type 2
Academic Dissertation
Portugal

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