| Popis: |
Apolipoprotein E (ApoE) is the major lipoprotein in the brain and connects metabolic interactions between astrocytes and neurons. The APOE4 isoform affects this function and represents a genetic predisposition for late-onset Alzheimer disease (AD), but the molecular mechanisms remain unclear. Lately, AD has been described as a metabolic disease and characterized by a lipid imbalance. The aim of this thesis was to elucidate how ApoE lipidation acts on the molecular mechanisms of AD. We have integrated cell-free in vitro assays, a new cell system based on isogenic iPSC-derived astrocytes and lipidomics to study ApoE lipidation, and how this is affected by genetic polymorphism. We show that astrocytes produce different types of ApoE-containing particles depending on their genotype and metabolic status. The molecular mechanisms discussed here provide a new model explaining the interaction between genetic polymorphism and environmental factors, such as dyslipidaemia or aging, in the aetiology of AD. |
