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<p>Sepsis-associated encephalopathy (SAE) is a critical complication of systemic inflammation with poorly understood mechanisms. This study identified adipocyte fatty acid-binding protein (A-FABP or FABP4) as a key mediator linking peripheral inflammation to central nervous system (CNS) damage. Using an LPS-induced endotoxemia model in wild-type and <i>Fabp4</i> knockout (KO) mice, we demonstrated that circulating A-FABP (1) crosses the compromised blood‒brain barrier (BBB), (2) accumulates in hippocampal neurons, and (3) synergizes with LPS to drive neuronal apoptosis. The monoclonal antibody 6H2, which neutralizes A-FABP, significantly alleviated BBB dysfunction, attenuated neuroinflammation, and improved neuronal survival. In vitro studies confirmed that HT22 neurons internalize exogenous A-FABP, which amplifies LPS-induced late apoptosis without affecting early apoptotic pathways. These findings establish circulating A-FABP as both a biomarker and therapeutic target for SAE, revealing a novel periphery-to-CNS inflammatory cascade.</p>

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Circulating adipocyte fatty acid-binding protein exacerbates LPS-induced neurotoxicity by crossing the disrupted blood–brain barrier and promoting neuronal apoptosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月23日

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  • Muhammad Mustapha Ibrahim,
  • Chunyan Li,
  • Linhui Qiu,
  • Yue Hu,
  • Aimin Xu,
  • Shilun Yang,
  • Junlei Chang,
  • Cheng Fang

摘要

Sepsis-associated encephalopathy (SAE) is a critical complication of systemic inflammation with poorly understood mechanisms. This study identified adipocyte fatty acid-binding protein (A-FABP or FABP4) as a key mediator linking peripheral inflammation to central nervous system (CNS) damage. Using an LPS-induced endotoxemia model in wild-type and Fabp4 knockout (KO) mice, we demonstrated that circulating A-FABP (1) crosses the compromised blood‒brain barrier (BBB), (2) accumulates in hippocampal neurons, and (3) synergizes with LPS to drive neuronal apoptosis. The monoclonal antibody 6H2, which neutralizes A-FABP, significantly alleviated BBB dysfunction, attenuated neuroinflammation, and improved neuronal survival. In vitro studies confirmed that HT22 neurons internalize exogenous A-FABP, which amplifies LPS-induced late apoptosis without affecting early apoptotic pathways. These findings establish circulating A-FABP as both a biomarker and therapeutic target for SAE, revealing a novel periphery-to-CNS inflammatory cascade.