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ePoster
HYPERAMMONEMIA INCREASES THE RELEASE OF PATHOLOGICAL EXTRACELLULAR VESICLES FROM MONOCYTES BY IMPAIRING LYSOSOMAL FUNCTION AND AUTOPHAGY THROUGH THE TNFΑ–CAMP–PKA–LC3 PATHWAY
Maria Pedrosa Sanchezand 3 co-authors
Centro de Investigación Príncipe Felipe
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS04-08PM-244
Presentation
Date TBA
Board: PS04-08PM-244
Event Information
Poster Board
PS04-08PM-244
Poster
View posterAbstract
Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE), a condition associated with peripheral inflammation. One mechanism by which peripheral alterations are transmitted to the brain is through extracellular vesicles (EV). Hyperammonemic rats are a model of MHE that reproduce cognitive impairment. Previous studies have shown that EV isolated from plasma or peripheral blood mononuclear cells (PBMC) of hyperammonemic rats induce neuroinflammation, neurotransmission alterations and cognitive impairment when injected into control rats. However, PBMC are a heterogeneous population. The aims of this study were: (1) to identify the PBMC subtype responsible for producing pathological EV in hyperammonemia; (2) to elucidate the mechanisms by which hyperammonemia increases EV release and promotes the formation of pathological EV in monocytes; and (3) to analyze the role of TNFα and protein kinase A (PKA).
EV were isolated from primary cultures of monocytes or CD4+ lymphocytes from control or hyperammonemic rats and added to hippocampal slices to evaluate neuroinflammation and neurotransmission. The involvement of TNFα and PKA was assessed by blocking TNFα or inhibiting PKA.
Monocytes, but not CD4+ lymphocytes, from hyperammonemic rats released pathological EV. Hyperammonemia increased EV release by monocytes and their content of TNFα and TNFR1. These EV activated glial cells, triggered the TNFα–TNFR1–S1PR2–IL-1β–CCL2–BDNF–TrkB pathway, and altered NMDA and AMPA receptor membrane expression. Mechanistically, increased TNFα elevated cAMP and PKA activity, leading to autophagy–lysosomal dysfunction, which enhanced EV release and pathogenic content. All effects were reversed by TNFα blockade or PKA inhibition.
EV were isolated from primary cultures of monocytes or CD4+ lymphocytes from control or hyperammonemic rats and added to hippocampal slices to evaluate neuroinflammation and neurotransmission. The involvement of TNFα and PKA was assessed by blocking TNFα or inhibiting PKA.
Monocytes, but not CD4+ lymphocytes, from hyperammonemic rats released pathological EV. Hyperammonemia increased EV release by monocytes and their content of TNFα and TNFR1. These EV activated glial cells, triggered the TNFα–TNFR1–S1PR2–IL-1β–CCL2–BDNF–TrkB pathway, and altered NMDA and AMPA receptor membrane expression. Mechanistically, increased TNFα elevated cAMP and PKA activity, leading to autophagy–lysosomal dysfunction, which enhanced EV release and pathogenic content. All effects were reversed by TNFα blockade or PKA inhibition.
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