中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (9): 4390-4405.doi: 10.4103/NRR.NRR-D-25-01313

• 原著:退行性病与再生 • 上一篇    下一篇

TAT-PBX1降低神经元胰岛素抵抗：恢复能量稳态缓解阿尔茨海默病

  

  • 出版日期:2026-09-15 发布日期:2026-05-22
  • 基金资助:
    梅杰登青年科学家学院与研究基金会（MJR202510105）；吉林省教育厅博士生科研创新计划资助（JJKH20250213BS）； 吉林大学博士生科研创新项目（2024KC137）；费和体质、营养与健康研究基金（CNS-Feihe2020A36）；中国青岛市自然科学基金（23–2–1-204-zyyd-jch）；中国国家自然科学基金（）82273673，82073581）

Trans-activator of transcription-pre-B-cell leukemia transcription factor 1 alleviates Alzheimer’s disease by reducing neuronal insulin resistance and restoring energy homeostasis

Xiangyuan Meng1, Zinan Liu1, Zhenhu Zhao1, Lei Chen2, Siyao Li1, Qi Song1, Ruihan Guo1, Xin Zhang1, Fanlei Meng3, Hui Zhang3, Li Tan3, Xinpeng Liu1, Yujie Wang1, Feng Zhong4, Run Liu4, Tianlin Gao4, *, Jinyu Liu1, *   

  1. 1School of Public Health, Jilin University, Changchun, Jilin Province, China; 
    2School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong Province, China; 
    3Institute of Agricultural Quality Standard and Testing Technology, Jilin Academy of Agricultural Sciences, Changchun, Jilin Province, China; 
    4School of Public Health, Qingdao University, Qingdao, Shandong Province, China
  • Online:2026-09-15 Published:2026-05-22
  • Contact: Tianlin Gao, PhD, MD, gaotl@qdu.edu.cn; Jinyu Liu, PhD, jy_liu@jlu.edu.cn.
  • Supported by:
    This work was supported by the Medjaden Academy & Research Foundation for Young Scientists, No. MJR202510105 (to XM); the Doctoral Research Innovation Program of the Jilin Provincial Department of Education, No. JJKH20250213BS (to XM); the Scientific Research Innovation Program for Doctoral Students, Jilin University, No. 2024KC137 (to XM); the Feihe Research Fund for Constitution, Nutrition, and Health, No. CNS-Feihe2020A36 (to FZ); the Natural Science Foundation of Qingdao in China, No. 23–2–1-204-zyyd-jch (to TG); the National Natural Science Foundation of China, Nos. 82273673 and 82073581 (both to JL).

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摘要：

阿尔茨海默病特征为海马神经元凋亡导致认知功能衰退。阿尔茨海默病病理主要由细胞代谢紊乱和神经元能量供给不足驱动，但现有治疗手段因副作用及疾病复杂性仍受限。越来越多的证据表明，β-淀粉样蛋白寡聚体诱导的神经元胰岛素抵抗和代谢功能障碍在阿尔茨海默病进展中起关键作用，但其潜在机制和治疗策略尚不明确。此转化性临床前研究结合病例对照分析、体外细胞检测及APP/PS1转基因小鼠体内实验，探究通过转录调控关键调节因子能否恢复神经元能量供给并改善阿尔茨海默病病理。研究将前B细胞白血病转录因子1（PBX1）识别为阿尔茨海默病脑代谢稳态的关键调节因子，开发了可穿透血脑屏障的TAT-PBX1融合蛋白以增强PBX1表达，旨在恢复神经元能量供给并减少细胞凋亡。机制研究表明，PBX1通过与胰岛素受体底物1启动子结合，转录上调其表达，从而增强阿尔茨海默病模型中的胰岛素信号传导。TAT-PBX1通过下调PDK4、显著上调丙酮酸脱氢酶表达并促进线粒体氧化磷酸化活性，抑制异常增强的糖酵解流并增加ATP生成，从而恢复神经元能量稳态。在APP/PS1转基因小鼠中治疗性给药TAT-PBX1后，认知功能显著改善，海马神经元凋亡减少，β-淀粉样蛋白沉积减轻。研究在给药剂量和时间窗口内未观察到显著肝毒性、肾毒性或其他可检测的不良反应。研究确证PBX1是阿尔茨海默病中神经元能量代谢的关键转录调控因子。研究阐明了PBX1-胰岛素受体底物1信号轴维持代谢稳态的分子机制。研究进一步证实，具有血脑屏障通透性的TAT-PBX1融合蛋白构成了一种机制创新且高度可转化的阿尔茨海默病治疗策略。


https://orcid.org/0000-0002-6831-1863 (Tianlin Gao); 

https://orcid.org/0000-0002-1000-9434 (Jinyu Liu)

关键词: 阿尔茨海默病lβ淀粉样蛋白寡聚体lAPP/PS1l胰岛素抵抗lIRS1l代谢重编程l分子医学l神经元l氧化磷酸化lPBX1

Abstract: Alzheimer’s disease is characterized by hippocampal neuronal apoptosis, which leads to cognitive decline. The pathophysiology of Alzheimer’s disease is largely driven by disrupted cellular metabolism and insufficient neuronal energy supply. However, current treatments for Alzheimer’s disease remain limited because of side effects and disease complexity. Increasing evidence suggests that amyloid-β oligomer-induced neuronal insulin resistance and metabolic dysfunction play key roles in Alzheimer’s disease progression, yet their underlying mechanisms and therapeutic strategies remain unclear. In this translational preclinical study, we combined a case-control analysis, in vitro cell assays, and in vivo experiments using amyloid precursor protein/presenilin 1 transgenic mice to investigate whether transcriptional regulation of key regulatory factors restores neuronal energy supply and improves Alzheimer’s disease-induced pathology. The case-control analysis identified pre-B-cell leukemia transcription factor 1 as a crucial regulator of brain metabolic homeostasis in Alzheimer’s disease. We developed a blood–brain barrier-permeable trans-activator of transcription-pre-B-cell leukemia transcription factor 1 fusion protein to enhance pre-B-cell leukemia transcription factor 1 expression, with the aim of restoring neuronal energy supply and reducing apoptosis. Mechanistic investigations using Alzheimer’s disease models revealed that pre-B-cell leukemia transcription factor 1 transcriptionally upregulates insulin receptor substrate 1 by interacting with its promoter, which resulted in augmented insulin signaling. Trans-activator of transcription-pre-B-cell leukemia transcription factor 1 downregulated PDK4, significantly upregulated the expression of pyruvate dehydrogenase, and promoted mitochondrial oxidative phosphorylation activity, which inhibited the abnormally enhanced glycolytic flux, increased adenosine triphosphate production, and ultimately helped restore neuronal energy homeostasis. Therapeutic administration of trans-activator of transcription-pre-B-cell leukemia transcription factor 1 in amyloid precursor protein/presenilin 1 transgenic mice significantly enhanced cognitive performance, diminished hippocampal neuronal apoptosis, and mitigated amyloid-β deposition. No significant hepatotoxicity, nephrotoxicity, or other detectable adverse effects were observed within the dose ranges and time windows of administration. Taken together, we identified pre-B-cell leukemia transcription factor 1 as a crucial transcriptional regulator of neuronal energy metabolism in Alzheimer’s disease. Moreover, we elucidated the molecular mechanism through which the pre-B-cell leukemia transcription factor 1–insulin receptor substrate 1 signaling axis sustains metabolic homeostasis. Furthermore, we demonstrated that the blood–brain barrier-permeable trans-activator of transcription-pre-B-cell leukemia transcription factor 1 fusion protein constitutes a mechanistically innovative and highly translatable therapeutic strategy for Alzheimer’s disease. 

Key words: Alzheimer’s diseasel amyloid-beta oligomersl amyloid precursor protein/presenilin 1l insulin receptor substrate 1l insulin resistancel metabolic reprogrammingl molecular medicinel neuronl oxidative phosphorylationl pre-B-cell leukemia transcription factor 1