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<p>Extracellular Tau determines the progression of Alzheimer’s disease, yet therapeutic strategies targeting it are hindered by poor brain delivery and limited clearance. Here we developed a Tau-clearing cell therapy based on monocytes functionalized with a high-affinity Tau-specific aptamer. The aptamer was covalently conjugated to the surface of monocytes (derived from bone marrow leucocytes and cultured under monocyte-inducing conditions) via bioorthogonal chemistry without affecting their viability or function. Upon intravenous administration in mice expressing mutant and disease-relevant human Tau, the engineered monocytes actively crossed the blood–brain barrier and accumulated in Tau-rich brain regions such as the hippocampus and striatum. They efficiently phagocytosed extracellular Tau, leading to a significant reduction in Tau burden. As a result, glial activation was suppressed, neuroinflammation was alleviated, and neuronal and mitochondrial integrity was preserved. Long-term treatment improved memory and spatial learning, without inducing toxicity or behavioural side effects. These results demonstrate that aptamer-guided monocytes can achieve targeted delivery, effective clearance and sustained neuroprotection, offering a promising strategy for therapeutic intervention in Alzheimer’s disease.</p>

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Targeted clearance of extracellular Tau using aptamer-armed monocytes alleviates neuroinflammation in mice with Alzheimer’s disease

  • 期刊论文

  • 发表日期：

    2025年10月1日

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  • Yuting Zhuo,
  • Yao Lu,
  • Yan Zhu,
  • Nachuan Wen,
  • Guangjing Zou,
  • Hongkun Lu,
  • Xinyu Pei,
  • Yutong Zhang,
  • Qiang Zhang,
  • Xin Wang,
  • Wenjuan Zhang,
  • Qingyang Zhang,
  • Zhimin Wang,
  • Sitao Xie,
  • Chang-Qi Li,
  • Weihong Tan,
  • Liping Qiu

摘要

Extracellular Tau determines the progression of Alzheimer’s disease, yet therapeutic strategies targeting it are hindered by poor brain delivery and limited clearance. Here we developed a Tau-clearing cell therapy based on monocytes functionalized with a high-affinity Tau-specific aptamer. The aptamer was covalently conjugated to the surface of monocytes (derived from bone marrow leucocytes and cultured under monocyte-inducing conditions) via bioorthogonal chemistry without affecting their viability or function. Upon intravenous administration in mice expressing mutant and disease-relevant human Tau, the engineered monocytes actively crossed the blood–brain barrier and accumulated in Tau-rich brain regions such as the hippocampus and striatum. They efficiently phagocytosed extracellular Tau, leading to a significant reduction in Tau burden. As a result, glial activation was suppressed, neuroinflammation was alleviated, and neuronal and mitochondrial integrity was preserved. Long-term treatment improved memory and spatial learning, without inducing toxicity or behavioural side effects. These results demonstrate that aptamer-guided monocytes can achieve targeted delivery, effective clearance and sustained neuroprotection, offering a promising strategy for therapeutic intervention in Alzheimer’s disease.