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

  • Neurobiol Dis. 2026 Aug:226:107470. doi: 10.1016/j.nbd.2026.107470.
Xiaotong Chen  1 ,  Yangyang Liu  2 ,  Xueting Song  1 ,  Jingyi Chen  1 ,  Haiyan Zhu  1 ,  Qiong Sun  1 ,  Zhijie Li  1 ,  Shan Zhao  1 ,  Changmei Zhang  3 ,  Lijie Wu  4
Affiliations
  • 1. Department of Children's and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150086, China; Heilongjiang Province Key Laboratory of Child Development and Genetic Research, Harbin Medical University, Harbin 150086, China.
  • 2. Department of Developmental Behavioral Pediatrics, the Sixth Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
  • 3. Department of Pharmaceutics, Harbin Medical University-Daqing Campus, 1 Xinyang Rd, Daqing 163319, China. Electronic address: [email protected].
  • 4. Department of Children's and Adolescent Health, Public Health College, Harbin Medical University, Harbin 150086, China; Heilongjiang Province Key Laboratory of Child Development and Genetic Research, Harbin Medical University, Harbin 150086, China; Department of Developmental Behavioral Pediatrics, the Sixth Affiliated Hospital of Harbin Medical University, Harbin 150086, China. Electronic address: [email protected].
PMID: 42248422 DOI: 10.1016/j.nbd.2026.107470
Abstract

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 is associated with hippocampal synaptic pathology and behavioral deficits in ASD, suggesting a potential mechanistic target for therapeutic intervention.

Keywords
APOE/S1P axis; Autism spectrum disorder; BTBR mice; Nanotherapeutic; PI3K/Akt/mTOR; Synaptic dysfunction.
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