The role of high-fat diet in an APP/PS1 model of familial Alzheimer disease = Efecto de una dieta rica en grasas en ratones APP/PS1, modelo familiar de la enfermedad de Alzheimer

• Autores: Dmitry Petrov
• Directores de la Tesis: Jaume Folch López (dir. tes.), Antoni Camins Espuny (dir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2015
• Idioma: inglés
• Tribunal Calificador de la Tesis: Jordi Camarasa (presid.), Coral Sanfeliu Pujol (secret.), Maria Teresa Colomina Fosch (voc.)
• Materias:
  • Ciencias de la vida
    • Biología animal (zoología)
      • Fisiología animal
• Enlaces
  • Tesis en acceso abierto en:  TDX  Dipòsit Digital de la UB 
• Resumen

  • Global obesity is a pandemic status, estimated to affect over 2 billion people, and has resulted in an enormous strain on healthcare systems worldwide. The situation is compounded by the fact that apart from the direct costs associated with overweight pathology, obesity presents itself with a number of comorbidities, including an increased risk for the development of neurodegenerative disorders. Alzheimer disease (AD), the main cause of senile dementia, is no exception. Spectacular failure of the pharmaceutical industry to come up with effective AD treatment strategies is forcing scientific community to rethink the underlying molecular mechanisms leading to cognitive decline. Research described in this doctoral thesis is focused on the effects of a high-fat diet (HFD) versus control chow in C57/Bl6 Wild-type (WT) and APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. WT and APP/PS1 mice were fed control chow from the time of weaning (21 days) until the age of 3 months. In addition, a separate group of animals were fed either a control or a HFD from the time of weaning until 6 months of age. We have detected tau hyperphosphorylation, amyloidogenesis and impaired mitochondrial signaling in the hippocampi of 3-month-old APP/PS1 mice. By the time the mice reached 6 months of age this phenotype was exacerbated. In addition, 6-month-old APP/PS1 mice present with cognitive deficits, hippocampal insulin signaling abnormalities and impairments in peripheral glucose and insulin tolerance. On a HFD, diet-induced obesity and metabolic syndrome were present both in the WT and APP/PS1 groups. Both groups demonstrate memory loss and impaired peripheral glucose metabolism as well as abnormal hippocampal insulin signaling and mitochondrial metabolism, with APP/PS1 mice exhibiting a nearly diabetic phenotype. Significantly higher levels of insoluble A? (1-42) were detected in the cortical extracts of HFD-fed APP/PS1 mice versus APP/PS1 animals on a control chow. In transgenic animals predisposed to AD development, the introduction of hypercaloric diet significantly worsened existing phenotype both at the periphery and in the hippocampal networks. Overall, our results suggest that metabolic syndrome, diabetes and related comorbidities clearly do have a potential to significantly worsen the symptoms of AD disease.