APOE2 Allele of APOE Makes Neurons More Resilient in Cell Cultures
The Apolipoprotein E (APOE) gene exhibits a small number of common sequence variants across the human population, of which the desirable APOE2 variant is associated with modestly greater longevity, and the undesirable APOE4 variant is associated with a sizable increase in the risk of Alzheimer's disease. APOE is one of only a few genes to exhibit a reliable correlation with human life expectancy that replicates in epidemiological data from multiple study populations. APOE is involved in the transport of lipids, particularly cholesterol, as a component part of different forms of transport particle that carry these molecules around the body, such as low density lipoprotein (LDL) particles. In this context it is important to note that the lipid manufacture and transport systems of the brain are somewhat distinct from those of the body, and APOE is involved separately on both sides of the blood-brain barrier.
Investigations into how exactly APOE variants affect Alzheimer's disease risk and progression have focused on lipid metabolism. It seems likely that APOE may have roles inside the cell as well as outside the cell, as few proteins have only a single function. Those roles are not well understood, however. A body of evidence links APOE to inflammatory behavior in immune cells, such as microglia in the brain, but it is not settled as to how exactly this emerges from or interacts with its role in lipid metabolism, or whether it is entirely distinct. To further complicate matters, today's open access paper provides cell culture data to show that APOE2 appears to reduce DNA damage and cellular senescence in neurons. The authors do not offer any mechanistic interpretation of this data, it is an observation only. It is definitely unclear as to how this outcome emerges given what is known of APOE.
APOE is a plasma glycoprotein critical for lipid transport and metabolism. In the central nervous system (CNS), it serves as the principal cholesterol carrier between astrocytes and neurons, supporting energy supply, synaptic remodeling, and neuronal repair. While astrocytes are the main producers of APOE in the CNS, neurons also express APOE under conditions of stress and aging. Given this background, we sought to evaluate the contribution of the APOE genotype to neuronal aging and vulnerability. Using bulk and single-cell RNA-sequencing (RNA-seq) of induced pluripotent stem cell derived GABAergic neurons, we identified genotype-dependent differences in gene expression and DNA damage pathways. Notably, APOE2 GABAergic neurons showed upregulated DNA repair signaling, and APOE4 neurons exhibited increased synaptic gene expression, DNA damage, and altered cell motility. In a separate model of Ngn2-induced glutamatergic neurons, APOE2 neurons resisted genotoxic stress and were less prone to acquiring a senescent-like phenotype than isogenic APOE3 and APOE4 neurons.
Consistent with these transcriptional and functional differences, APOE2 neurons displayed smaller nucleoli and preserved nuclear lamina integrity - features linked to longevity and genomic stability - while APOE4 neurons showed enlarged nucleoli and increased senescence-associated markers. Importantly, these anti-aging molecular features were recapitulated in the hippocampus of aged APOE2 knock-in mice, supporting the in vivo relevance of our findings. Together, these results suggest that APOE genotype shapes neuronal aging through differential regulation of DNA damage responses and nuclear homeostasis.
Aging and neurodegenerative diseases are marked by genomic instability in neurons, including dysregulation of repetitive elements expression and activity. In senescent human mesenchymal progenitor cells, the accumulation of APOE drives increased expression of repetitive elements. Additionally, ribosomal RNA production increases with age, leading to enhanced ribosome biogenesis, increased protein translation, and intracellular energy depletion. In our study, analysis of repetitive elements in GABAergic neurons revealed increased ribosomal RNA expression in APOE4 genotype under non-stress conditions, suggesting that APOE alleles differentially influence nucleolar activity.
Collectively, our findings support a model in which the APOE genotype influences neuronal aging trajectories through regulation of genomic stability.