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

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.

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Publication Details

Journal
Journal of Neuroinflammation
Published
2025-11-10
DOI
https://doi.org/10.1186/s12974-025-03588-z
Citations
1
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
Field-Weighted Citation Impact
0.84

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article

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

Joana R. Guedes, Xianshu Bai, Teresa Canedo, Teresa Summavielle et al.
1 citations
Journal of Neuroinflammation
Neuroinflammation and Neurodegeneration Mechanisms
0.84
article

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

Joana R. Guedes, Xianshu Bai, Teresa Canedo, Teresa Summavielle, Boris Rubinstein, Joana Tedim-Moreira, Jéssica Costa, Irina S. Moreira, João Peça, Inês Mendes Pinto, Tiago O. Almeida, Ana Magalhães, Renato Socodato, João B. Relvas, Frank Kirchhoff, Camila C. Portugal, Cátia Silva, João Wesley da Silva Galvão
article en
1 citations

Abstract

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.

Journal of NeuroinflammationVol. 22(1)
Stowers Institute for Medical Research (US), Universidade do Porto (PT), International Iberian Nanotechnology Laboratory (PT), i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT), Instituto de Biología Molecular y Celular de Plantas (ES), Instituto de Biologia Molecular e Celular, University of Coimbra (PT), Saarland University (DE), University of Minho (PT)
European Commission, Ministério da Ciência, Tecnologia e Ensino Superior, Fundação para a Ciência e a Tecnologia, European Regional Development Fund
Openalex Percentile: Top 20%
Neuroinflammation and Neurodegeneration Mechanisms
0.84
DOIOpen Access PDFOpenAlex
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