Apolipoprotein E2 expression drives increased brain exosome levels during aging to mitigate neuronal endosomal dysfunction

The polymorphic APOE gene is the greatest genetic determinant of sporadic Alzheimer’s disease risk: the APOE4 allele increases risk while the APOE2 allele is neuroprotective compared with the risk-neutral APOE3 allele. The neuronal endosomal system is inherently vulnerable during aging, and APOE4 exacerbates this vulnerability by driving an enlargement of early endosomes and reducing exosome release in humans and mice. We hypothesized that the protective effects of APOE2 are mediated through the endosomal pathway during aging. In contrast to Alzheimer’s disease and APOE4 models, we detected normal morphology and abundance of early endosomes within cortical neurons of APOE2 targeted-replacement mice during aging despite decreased rab5b recruitment to early endosomes. Similarly, the morphology and abundance of retromer-associated vesicles was normal in APOE2 mice, despite reduced recruitment of vesicle-associated VPS35. Significantly, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, indicative of an enhanced endosomal cargo clearance to the extracellular space that contributes to a homeostatic balance of endosomal functions. Our findings thus demonstrate that APOE2 effectively offsets endosomal pathway changes during aging to preserve its integrity by enhancing exosome biogenesis, mitigating age-driven endosomal dysfunction that contributes to Alzheimer’s disease risk.