Molecular Horizons - Helena Anastacio, PhD Exit Seminar

Alzheimer’s disease (AD) is the most common type of dementia and the most prevalent neurodegenerative disease globally. Yet, no cure is available and current treatments are limited. Memory formation and learning, both of which are impaired in AD, require adequate levels of the neurotransmitter glutamate. However, elevated glutamate can promote cell death via excessive calcium (Ca2+) influx through ionotropic glutamate receptors (iGluRs). These receptors can be modulated by alterations in the lipid membrane, which may arise from increased lipid peroxidation, a hallmark of AD. The lipid antioxidant enzyme glutathione peroxidase 4 (GPX4) can mitigate membrane lipid peroxidation, but its role in AD remains underexplored. To better understand these phenotypes, this thesis used induced pluripotent stem cell (iPSC) derived-neurons and human postmortem brain tissue from AD patients to investigate neuronal Ca2+ signals, membrane lipid profile and GPX4 expression. This study revealed that AD neurons had higher Ca2+ responses to glutamate and the iGluR agonist, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Additionally, AD iPSCs displayed a significant reduction of various lipid species. However, no significant changes in GPX4 levels were detected between AD and controls. Together, these findings highlight a potential role for aberrant neuronal Ca2+ signals and membrane lipid composition in AD.