Effects of Aβ40 and Aβ42 peptides on Human Neural Stem Cell biology and the generation of human brain organoids

• Autores: Adela María Bernabeu Zornoza
• Directores de la Tesis: Isabel Liste Noya (dir. tes.), Alberto Serrano Martínez (tut. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2020
• Idioma: inglés
• Número de páginas: 233
• Títulos paralelos:
  • Efectos de los péptidos Ab40 y Ab42 en la biología de las células madre neurales humanas y la generación de organoides cerebrales humanos
• Tribunal Calificador de la Tesis: Asia Fernández Carvajal (presid.), María Jesús Bullido Gómez -Heras (secret.), J. Carlos Villaescusa (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline that represents the most common cause of dementia in the elderly population. One of the main histopathologic features of AD is the formation and accumulation of amyloid plaques in the brain. They are formed by extracellular fibrillary aggregates of amyloid-β peptides (Aβ) generated by the enzymatic processing of amyloid precursor protein (APP).

    Aβ40 and Aβ42 peptides are the main isoforms found in these amyloid plaques. Although considered neurotoxic, Aβ peptides also play an important biological role in the adult brain and during embryonic brain development. However, the physiological function of these Aβ peptides remains poorly understood and results are controversial. Aβ peptides can be detected in non-aggregated (monomeric) and aggregated forms (oligomeric and fibrillary) and each form has different cytotoxic and physiological properties.

    In order to better understand the physiological/pathological role of these Aβ peptides, in this thesis, we studied the effects of both Aβ peptides (Aβ40 and Aβ42) at different concentrations and different aggregation states (monomeric, oligomeric and fibrillary), on cell death, cell proliferation and cell fate specification of human neural stem cells (human NSCs) by immunocytochemistry and qRT-PCR. Our results showed that higher concentrations of both Aβ peptides are cytotoxic for these cells in all cases, but the fibrillary form is the most toxic. Regarding cell proliferation, we observed a significant increase after treatment with both Aβ peptides in monomeric form; however, we observed a decrease or no change when we studied the other forms. Finally, concerning cell fate specification, our data showed that treatment with Aβ peptides, in all states tested, significantly affects differentiation of human NSCs. Together, our results suggest that Aβ peptides affect human NSCs biology and provide us with information about their physiological/pathological role.

    NSCs have the capability of self-renewal and differentiate into functional glial and neuronal cells, making these cells a good tool for the study of neurodegenerative diseases and for future therapeutic applications in diseases such as AD. However, although highly valuable, they are devoid of the tridimensional component necessary for normal organ development. It has recently been described that pluripotent stem cells in a suitable environment are capable of generating three-dimensional (3D) structures called "cerebral organoids”. These 3D structures have revealed important similarities and differences between their development and that of the brain in vivo, and therefore represent a promising in vitro model to understand how the brain develops, to study the physiological pathways during development and the molecular pathology associated with neurodegenerative disorders, such as AD