Apolipoprotein E2 Expression Alters Endosomal Pathways in a Mouse Model With Increased Brain Exosome Levels During Aging

ABSTRACT 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 the brain of humans and mice. We hypothesized that the protective effects of APOE2 are, in part, mediated through the endosomal pathway. Messenger RNA analyses showed that APOE2 leads to an enrichment of endosomal pathways in the brain when compared with both APOE3 and APOE4. Moreover, we show age‐dependent alterations in the recruitment of key endosomal regulatory proteins to vesicle compartments when comparing APOE2 to APOE3. In contrast to the early endosome enlargement previously shown in Alzheimer's disease and APOE4 models, we detected similar morphology and abundance of early endosomes and retromer‐associated vesicles within cortical neurons of aged APOE2 targeted‐replacement mice compared with APOE3. Additionally, we observed increased brain extracellular levels of endosome‐derived exosomes in APOE2 compared with APOE3 mice during aging, consistent with enhanced endosomal cargo clearance by exosomes to the extracellular space. Our findings thus demonstrate that APOE2 enhances an endosomal clearance pathway, which has been shown to be impaired by APOE4 and which may be protective due to APOE2 expression during brain aging. 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. In contrast to APOE4’s detrimental effects on endosomal pathways, aged APOE2 mice brains show endosomal pathway resiliance, stable endosome morphology, and higher exosome levels. These findings argue that the APOE2 allele enhances endosomal cargo clearance to mitigate aging‐related neuronal vulnerabilities that increase the risk of Alzheimer’s disease.