Hippocampal APOE/S1P axis regulates synaptic and behavioral deficits in a mouse model of autism

Autism spectrum disorder (ASD) is a neurodevelopmental condition of unknown mechanism. Synaptic pathology is a core feature, but the key molecular regulators are unclear. The brain's major apolipoprotein APOE transports lipids including S1P to regulate neuronal function; however, the role of the APOE/S1P axis in ASD is unknown. Here, we found that serum APOE and S1P were elevated in children with ASD. In the BTBR mouse hippocampus, both were also elevated, with abnormal APOE aggregation on neurons. To test causality, we developed a brain-targeted nanomicelle (MAN@SKI II) that inhibits hippocampal S1P. MAN@SKI II lowered APOE/S1P levels, reactivated the PI3K/Akt/mTOR pathway, repaired synaptic ultrastructure, and improved social and cognitive behaviors in BTBR mice. Together, these findings indicate that the APOE/S1P axis plays a regulatory role in hippocampal synaptic pathology and behavioral deficits in ASD, suggesting a potential mechanistic target for therapeutic intervention.