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SPIKE PROTEIN DRIVES SYNAPTIC DEFICITS AND INFLAMMATORY MICROGLIA THROUGH A TLR4-DEPENDENT MECHANISM IN HIPPOCAMPAL SLICES
Dalila Mangoand 4 co-authors
University of Rome "Tor Vergata"
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS02-07PM-413
Presentation
Date TBA
Board: PS02-07PM-413
Event Information
Poster Board
PS02-07PM-413
Poster
View posterAbstract
Aim: Clinical observations report the association of COVID-19 with neurodegenerative disorders and cognitive defects. This characteristic phenomenon, called “Long COVID” encompasses persistent neurological symptomatology including cognitive impairment, neuropsychiatry disorders as anxiety and depression. In a novel ex vivo Neuro COVID model we investigated Toll like receptor 4 (TLR4) as a mediator of SARS-CoV-2 induced neuroinflammation.
Methods: Hippocampal mouse slices (from both male and female, 30-45 days) were treated with Spike Protein (SP) alone or co treated with the selective TLR4 antagonist TAK-242. Glial responses, cytokine production (IL 1β, IL 6, TNF α, IFN γ), ROS levels, and synaptic plasticity (LTP) were assessed using cellular, biochemical, and electrophysiological approaches.
Results: SP induced glial activation, elevated proinflammatory cytokines and ROS, and significantly reduced LTP. Pharmacological blockade of TLR4 with TAK-242 effectively attenuated glial reactivity, normalized inflammatory markers, reduced ROS production, and fully restored LTP to control levels.
Conclusions: These findings identify TLR4 as a key mediator of SP induced neuroinflammation and synaptic impairment. The ex vivo preparation demonstrates high suitability for mechanistic dissection of SARS-CoV-2 related neurological alterations and for preclinical testing of therapeutic strategies targeting neuroimmune pathways. Understanding the signaling pathways activated by viral components such as the SP is essential to unravel the mechanisms contributing to cognitive symptoms in Long COVID.
Methods: Hippocampal mouse slices (from both male and female, 30-45 days) were treated with Spike Protein (SP) alone or co treated with the selective TLR4 antagonist TAK-242. Glial responses, cytokine production (IL 1β, IL 6, TNF α, IFN γ), ROS levels, and synaptic plasticity (LTP) were assessed using cellular, biochemical, and electrophysiological approaches.
Results: SP induced glial activation, elevated proinflammatory cytokines and ROS, and significantly reduced LTP. Pharmacological blockade of TLR4 with TAK-242 effectively attenuated glial reactivity, normalized inflammatory markers, reduced ROS production, and fully restored LTP to control levels.
Conclusions: These findings identify TLR4 as a key mediator of SP induced neuroinflammation and synaptic impairment. The ex vivo preparation demonstrates high suitability for mechanistic dissection of SARS-CoV-2 related neurological alterations and for preclinical testing of therapeutic strategies targeting neuroimmune pathways. Understanding the signaling pathways activated by viral components such as the SP is essential to unravel the mechanisms contributing to cognitive symptoms in Long COVID.
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