RT info:eu-repo/semantics/doctoralThesis
T1 Role of intracellular calcium and novel neuroprotective strategies against amyloid peptide and SARS-CoV-2 viroporin E.
A1 López Vázquez, Sara
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Alzheimer
K1 Calcium
K1 Calcio
K1 Alzheimer's Disease
K1 Enfermedad de Alzheimer
K1 COVID-19
K1 COVID-19
K1 Neuroprotection
K1 Neuroprotección
K1 2411 Fisiología Humana
AB Neurodegenerative diseases are a growing challenge due to their increasing prevalence, largely driven by the ageing population. These diseases are characterized by the progressive deterioration of the central nervous system, with Alzheimer’s disease being one of the most common, which leads into cognitive decline. Additionally, COVID-19 shares similarities with these conditions, as it can affect the nervous system, and ageing is a known risk factor. Two key factors involved in neurodegenerative processes are disruptions in Ca²⁺ homeostasis and neuronal death.Within this context, the objective of this doctoral research is to elucidate alterations in intracellular Ca²⁺ homeostasis and investigate its role in the mechanism of action of novel neuroprotective strategies against amyloid β oligomers in Alzheimer's disease and the SARS-CoV-2 E viroporin in COVID-19.Novel molecules with a heterocyclic structure have been proposed in this research as potential neuroprotectors against Alzheimer's disease due to their ability to reduce neuronal death induced by NMDA-mediated excitotoxicity and amyloid β oligomers, as well as their capacity to modulate Ca²⁺ signalling. Additionally, the neuroprotective role of acetylcholine in ageing hippocampal neurons has been demonstrated.Astrocytes are the most abundant cell type in the central nervous system, and unlike neurons, this thesis highlights that their exposure to amyloid β oligomers does not induce cell death. However, astrocytes do experience alterations in redox levels and intracellular Ca²⁺ stores. Furthermore, the transfer of healthy mitochondria to amyloid β-treated astrocytes is proposed as a strategy to reverse the changes in intracellular Ca²⁺ stores.The E viroporin, like amyloid β oligomers, induces cell death in aged neurons but not in young neurons or astrocytes. Moreover, it has been shown to disrupt Ca²⁺ homeostasis by triggering the release of Ca²⁺ from stores and other additional Ca²⁺ events. Interestingly, Aplidin has demonstrated potential in preventing the death of aged hippocampal neurons and reducing the Ca²⁺ release from stores induced by the E protein. However, the combination of E protein and amyloid β oligomers does not have a summative effect on neuronal toxicity.In conclusion, both amyloid β oligomers and the SARS-CoV-2 E viroporin induce cell death in aged neurons but not in astrocytes, along with disrupting Ca²⁺ homeostasis. Strategies such as novel molecules, existing drugs, or mitocondrial transfer are proposed as potential therapies for Alzheimer's disease and COVID-19. 
YR 2024
FD 2024
LK https://uvadoc.uva.es/handle/10324/76332
UL https://uvadoc.uva.es/handle/10324/76332
LA eng
NO Escuela de Doctorado
DS UVaDOC
RD 19-jul-2025