Deans' stroke musings: Profilin 1 Controls a Microglial Cytoskeleton Checkpoint to Prevent Senescence and Premature Synaptic Decline

Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Sunday, August 31, 2025

Profilin 1 Controls a Microglial Cytoskeleton Checkpoint to Prevent Senescence and Premature Synaptic Decline

Will your competent? doctor and hospital ensure human testing gets done? NO? So, NOTHING RESEMBLING COMPETENCE ANYWHERE IN YOUR STROKE HOSPITAL? RUN AWAY!

Profilin 1 Controls a Microglial Cytoskeleton Checkpoint to Prevent Senescence and Premature Synaptic Decline

Camila Cabral Portugal1

Tiago Oliveira Almeida1

Joana Tedim-Moreira1

Cátia Silva1

Teresa Canedo1

João Galvão1

Ana Magalhães1

Teresa Summavielle1

Xianshu Bai2

Frank Kirchhoff2

Boris Rubinstein3

Irina Moreira4

Jéssica Costa4

Joana Guedes4

Inês Mendes Pinto1

João Peça4

Renato Socodato1

João Bettencourt Relvas1

1 Universidade do Porto,

2 Saarland University,

3 Stowers Institute for Medical Research,

4 University of Coimbra

https://doi.org/10.21203/rs.3.rs-6666431/v1

This work is licensed under a CC BY 4.0 License

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, without developmental or chronic aging confounders. Using a multi-omics approach combined with intravital two-photon imaging, we found that Pfn1 ablation disrupts actin–microtubule coupling and impairs microglial morphodynamics, leading to 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 decrease in the frequency of GABAergic inhibitory postsynaptic currents in the prefrontal cortex. These circuit-level disturbances ultimately manifest as alterations in anxiety and risk-taking behaviors. 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.