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<p>Profilin 1 (Pfn1) expression decreases significantly in aged human microglia, suggesting that loss of cytoskeletal integrity may trigger microglial senescence and increased synaptic vulnerability. To test this hypothesis, we used an inducible, microglia-specific Pfn1 knockout in adult mice, a strategy designed to isolate the direct effects of acute Pfn1 loss at the cellular and circuit levels, avoiding confounding factors from development or chronic aging. Using a multi-omics approach combined with intravital two-photon imaging, we found that Pfn1 ablation disrupts actin–microtubule coupling, leading to a collapse of microglial morphodynamics and a complete failure to respond to focal brain injury. This cytoskeletal disruption triggers a cell-autonomous, senescence-associated secretory phenotype (SASP), driven by the ERK/NF-κB signaling axis. SASP factors secreted by Pfn1-deficient microglia reprogram the synaptic environment, resulting in significant deficits in mitochondrial energy production and a selective reduction in the frequency of GABAergic inhibitory postsynaptic currents in the prefrontal cortex. These circuit-level disturbances lead to behaviors characterized by altered anxiety and risk assessment. Our findings identify Pfn1 as a critical checkpoint against microglial senescence and show that its loss is sufficient to drive circuit-specific synaptic decline, highlighting the Pfn1-cytoskeleton axis as a potential therapeutic target to enhance brain resilience.</p>

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Profilin 1 controls a microglial cytoskeleton checkpoint to prevent senescence and premature synaptic decline

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月10日

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  • Camila Cabral Portugal,
  • Tiago Oliveira Almeida,
  • Joana Tedim-Moreira,
  • Cátia Silva,
  • Teresa Canedo,
  • João Galvão,
  • Ana Magalhães,
  • Teresa Summavielle,
  • Xianshu Bai,
  • Frank Kirchhoff,
  • Boris Rubinstein,
  • Irina Moreira,
  • Jéssica Costa,
  • Joana Guedes,
  • Inês Mendes Pinto,
  • João Peça,
  • Renato Socodato,
  • João Bettencourt Relvas

摘要

Profilin 1 (Pfn1) expression decreases significantly in aged human microglia, suggesting that loss of cytoskeletal integrity may trigger microglial senescence and increased synaptic vulnerability. To test this hypothesis, we used an inducible, microglia-specific Pfn1 knockout in adult mice, a strategy designed to isolate the direct effects of acute Pfn1 loss at the cellular and circuit levels, avoiding confounding factors from development or chronic aging. Using a multi-omics approach combined with intravital two-photon imaging, we found that Pfn1 ablation disrupts actin–microtubule coupling, leading to a collapse of microglial morphodynamics and a complete failure to respond to focal brain injury. This cytoskeletal disruption triggers a cell-autonomous, senescence-associated secretory phenotype (SASP), driven by the ERK/NF-κB signaling axis. SASP factors secreted by Pfn1-deficient microglia reprogram the synaptic environment, resulting in significant deficits in mitochondrial energy production and a selective reduction in the frequency of GABAergic inhibitory postsynaptic currents in the prefrontal cortex. These circuit-level disturbances lead to behaviors characterized by altered anxiety and risk assessment. Our findings identify Pfn1 as a critical checkpoint against microglial senescence and show that its loss is sufficient to drive circuit-specific synaptic decline, highlighting the Pfn1-cytoskeleton axis as a potential therapeutic target to enhance brain resilience.