AD risk variants in APOE differentially affect lipid metabolism in iPSC derived neurons, astrocytes and microglia
Femke M Feringa, Amir Abou Elmagd, Iris Daphne Kruijff, Jorin Heijneman, Sascha Koppes, Yassene Mohammed, Martin Giera, Rik van der Kant- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Despite the clear function of APOE as a lipid carrier it is still unclear how Alzheimer’s disease (AD) risk variants of APOE affect the lipidome of individual human brain cell types. In addition, while APOE is crucial for transport of cholesterol from astrocytes to neurons, a role for APOE in lipid transport in the opposite direction from neurons to astrocytes has recently been suggested.
Method
To generate an atlas of the lipidome of the APOE genotype in a cell type specific manner, we performed lipidomic analysis on iPSC‐derived neurons, astrocytes and microglia with a different APOE genetic background. By co‐culture of these different cell types we studied the impact of APOE genotype on lipid transport between neurons and glia. We determined how the glial immune response and neuronal AD pathology are impacted by the changes in lipid transport.
Result
We find that APOE genotype affects the lipidome in all tested brain cell types. Also, we identify cell type specific metabolic adaptations to APOE genotype, emphasizing the need to study APOE biology in the context of individual cell types. In co‐culture we find that iPSC‐derived neurons can transport fatty acids and cholesterol to astrocytes as well as microglia. This neuron to glia lipid transport route is affected by the AD risk variant APOE4, which might impact immune responses in the glia.
Conclusion
AD risk variants in APOE differentially affect lipid metabolism in iPSC‐derived neurons, astrocytes and microglia and alter neuronal to glial lipid transport.