Inhibition of TBK1 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathies

摘要

Investigating the contribution of astrocytic cholesterol transport in neuronal AB generation using human-induced pluripotent stem cells Alzheimer’s disease (AD) is the most common form of irre- versible dementia characterized by progressive neurodegeneration and accumulation of AB plaques. In brain, neurons are the major source of AB, and cholesterol-rich membrane domains, lipid rafts are thought to offer a structural platform for AB generation and aggregation. Previous study showed increased cholesterol levels in human induced pluripotent stem cell (iPSC)-derived astrocytes car- rying APOE4 variant compared to its APOE3 astrocytes. We aimed to address the role of hiPSC-derived astrocytes with APOEF4 alle- les on the formation of lipid rafts and AB production in neurons. By performing lipidomic analysis, we first examined differentially secreted lipid metabolites by APOE isoforms. We found that choles- terol is the one of the up-regulated metabolites by APOF4 variant in astrocytes. To investigate the effect of astrocytic cholesterol transport to neurons, we applied cholesterol or inhibitor of choles- terol synthesis (MACD) to rat primary neurons and measured the area and intensity of lipid rafts on plasma membrane. Cholesterol- treated neurons displayed increased area and intensity compared to non-treated neurons, whereas inhibition of cholesterol synthesis showed opposite phenotypes. We further observed that lipid rafts in rat primary neurons were indeed regulated by APOE isoform when they were co-culture with hiPSC-derived astrocytes carry- ing either APOE3 or APOF4 alleles. We are currently investigating whether cholesterol dysregulation in APOE4 astrocytes is sufficient to alter neuronal Af production, which will be presented at the meeting.