The role of plasmalogen lipids in synaptic assembly and function: Implications for neurodegenerative processes

Abstract

Synaptic dysfunction is a hallmark of neurodegeneration and often precedes neuronal death. Plasmalogen lipids, abundant in the brain, have a unique conical structure that supports vesicle fusion and fission, processes essential for synaptic transmission. Declining plasmalogen levels are observed with normal aging and are further exacerbated in Alzheimer’s disease (AD), particularly in carriers of the apolipoprotein E4 (APOE4) allele, the strongest genetic risk factor for late-onset AD.However, the precise role of plasmalogens in neuronal function and neurodegeneration remains unclear. This thesis aimed to elucidate the role of plasmalogens in synaptic assembly, neuronal differentiation, and their potential involvement in reactive oxygen species (ROS)-driven neuroinflammatory processes.To explore the functional significance of plasmalogens, SH-SY5Y cells with silenced fatty acyl CoA reductase 1 (FAR1), the rate-limitng enzyme in plasmalogen biosynthesis, were differentiated into neuron-like cells and assessed for protein expression and synapse assembly. Impaired clustering of the presynaptic protein Synaptophysin 1 in FAR1 knockdown cells revealed a critical role for plasmalogens in synaptic assembly. Further analyses suggested that plasmalogen depletion alters vesicle size, influences ROS degradation, and disrupts early neuronal differentiation, likely impairing cell adhesion.Additionally, this thesis introduces a cost-effective method for generating astrocytelike cells from ReNcell VM progenitors and co-culturing them with iPSC-derived neurons. This innovative approach provides a versatile platform for studying astrocytic lipid trafficking and the impact of APOE, the only lipid transport protein in the human brain and a key genetic risk factor for AD, on neuronal health.In summary, this work underscores the essential role of plasmalogen lipids in neuronal differentiation and synaptic function while establishing valuable methodologies for studying neuron-astrocyte interactions. These findings provide a foundation for future research into the molecular mechanisms of neurodegeneration, aging, and APOE-dependent lipid dysregulation, opening new avenues fortherapeutic strategies