Ceramide synthesis in Alzheimer's disease; from small extracellular vesicles to the development of the pathology in a mouse model

BELLOTTO M; BENTIVEGNA M; GREGOSA A; POMILIO C; GONZALEZ PEREZ N; PRESA J; SARAVIA F; BEAUQUIS J; VINUESA A

Porto

Congreso; ISN-ESN 2023 Meeting; 2023

International Society for Neurochemistry

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and the leading cause of dementia. One of its main hallmarks is the deposition of amyloid B (AB) in the brain. There is evidence of high levels of ceramides in plasma and CSF of AD patients.Ceramides are lipids that act as mediators of inflammation and in the production of extracellular vesicles, which are fundamental for intercellular communication. Previously, we have shown that small extracellular vesicles (SEVs) propagate inflammatory signals between microglia and neurons in vitro.In the present work, we aimed to study (1) the effects of inhibiting ceramide synthesis in an AD murine model. (2) the impact of Aß and palmitate (PA), a ceramide precursor, on glial activation and communication via SEVs.For our in vivo objective, we administered Myriocin (1 mg/kg/dose, nine doses) to 8-m-old PDAPP-J20 transgenic mice and characterized their cognitive capacity. After euthanasia, glial and neuronal parameters were analyzed. Transgenic mice of this age show hippocampal amyloid pathology, glial reactivity and cognitive deficits.For our in vitro objective, we extracted and analyzed SEVs-enriched fractions derived from the conditioned media of Aß- or PA-treated BV2 microglia. Enriched fractions were analyzed by dynamic light scattering (DLS) and flow cytometry. Results suggest that PA can increase the secretion of SEVs. Treatment of C6 astrocytes with PA failed to induce IL1B expression, a pro-inflammatory cytokine.However, conditioned media from PA-exposed microglia did (p