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<p>Microglial deformation and migration represent the final stages of inflammatory cytokines release, a key contributor to Alzheimer's disease (AD) pathology. However, the upstream regulators that initiate these morphological and functional changes in microglia remain unclear. In this study, we observed marked cytoskeletal reorganization in the hippocampal microglia of 2VO rats at 8&#xa0;weeks, indicative of a shift from a homeostatic to a pro-inflammatory state. Notably, <i>Tincr</i> expression was significantly downregulated in both the microglia of 2VO rats and the hippocampi of AD patients. <i>Tincr</i> knockdown promoted microglial deformation and migration, accompanied by enhanced cytokines release and phagocytic capacity. These morphological changes correlated with redistribution of non-muscle myosin IIA ( NM IIA) and reduced expression of MYPT1, both in vitro and in vivo, effects that were reversed by <i>Tincr</i> overexpression. Genetic rescue of <i>Mypt1</i> restored MYPT1 levels and attenuated <i>Tincr</i>-deficiency-induced microglial deformation in the hippocampi of 5xFAD mice. Mechanistically, <i>Tincr</i> enhanced MYPT1 protein expression through dual: functioning as a competing endogenous RNA (ceRNA) that sponged <i>miR-153-3p</i>, and serving as a direct protein-binding scaffold for MYPT1, thereby suppressing NM IIA phosphorylation and stabilizing microglial structure. These findings identify the <i>Tincr-</i>MYPT1<i>-NM IIA</i> axis as a critical regulatory pathway underlying chronic cerebral hypoperfusion (CCH)-induced microglial deformation and dysfunction, offering a novel mechanistic insight into the pathogenesis of neuroinflammation in AD.</p>

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Tincr protects against cognitive decline by upregulating MYPT1 mediated phosphorylation of structural protein NM IIA in microglia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月30日

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  • Qin Wang,
  • Liyang Sun,
  • Jing Ma,
  • Aiping Qiu,
  • Guitian Cong,
  • Xiaobin An,
  • Yang Qu,
  • Mingyou Zhang,
  • Xuqiao Wang,
  • Lu Zeng,
  • Jinan Yang,
  • Yan Wu,
  • Haining Chen,
  • Jiaqi Liu,
  • Fucong Han,
  • Dongyang Wang,
  • Tao Wang,
  • Jing Ai

摘要

Microglial deformation and migration represent the final stages of inflammatory cytokines release, a key contributor to Alzheimer's disease (AD) pathology. However, the upstream regulators that initiate these morphological and functional changes in microglia remain unclear. In this study, we observed marked cytoskeletal reorganization in the hippocampal microglia of 2VO rats at 8 weeks, indicative of a shift from a homeostatic to a pro-inflammatory state. Notably, Tincr expression was significantly downregulated in both the microglia of 2VO rats and the hippocampi of AD patients. Tincr knockdown promoted microglial deformation and migration, accompanied by enhanced cytokines release and phagocytic capacity. These morphological changes correlated with redistribution of non-muscle myosin IIA ( NM IIA) and reduced expression of MYPT1, both in vitro and in vivo, effects that were reversed by Tincr overexpression. Genetic rescue of Mypt1 restored MYPT1 levels and attenuated Tincr-deficiency-induced microglial deformation in the hippocampi of 5xFAD mice. Mechanistically, Tincr enhanced MYPT1 protein expression through dual: functioning as a competing endogenous RNA (ceRNA) that sponged miR-153-3p, and serving as a direct protein-binding scaffold for MYPT1, thereby suppressing NM IIA phosphorylation and stabilizing microglial structure. These findings identify the Tincr-MYPT1-NM IIA axis as a critical regulatory pathway underlying chronic cerebral hypoperfusion (CCH)-induced microglial deformation and dysfunction, offering a novel mechanistic insight into the pathogenesis of neuroinflammation in AD.