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bioRxiv · 10.1101/2024.03.07.583670

Cortical lipids containing choline mediate cannabinoid-induced cognitive improvement

Moreno-Rodriguez, M.·Martinez-Gardeazabal, J.·Bengoetxea de Tena, I.·Llorente-Ovejero, A.·Lombardero, L.·Gonzalez de San Roman, E.·Manuel, I.·Gimenez-Llort, L.·Rodriguez-Puertas, R.
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Abstract

Recent research connecting choline-containing lipids to basal forebrain cholinergic neurons (BFCN) degeneration in neuropathological states highlights a challenge for balancing lipid integrity with optimal acetylcholine (ACh) levels. Warranting an adequate choline source to maintain ACh levels in this pathway is crucial for preserving memory. The endocannabinoid (eCB) system plays a role in modulating learning and memory processes controlled by cholinergic neurotransmission. Consequently, we propose that activation of this system is neuroprotective against cholinergic degeneration. In the present study, we investigated the neuroprotective effect of a subchronic treatment with the CB1 cannabinoid agonist, WIN55,212-2, using both ex vivo and in vivo 192IgG-Saporin models of specific cholinergic damage. Degeneration of baso-cortical cholinergic pathways induced memory deficits and a downregulation of saturated and mono-unsaturated lysophosphatidylcholines (LPC) cortical levels. WIN55,212-2 not only restored memory deficits but also increased cortical ACh levels and modified cortical choline-containing lipids such as sphingomyelins (SM) and LPCs, which are essential for correct memory functioning, in lesioned animals. Given these results, we propose that WIN55,212-2 generates an alternative choline source through the breakdown of SMs, which is enough to increase cortical ACh levels and LPCs. These findings suggest that modification of choline-containing lipids by the activation of CB1 receptors is a promising therapy for dementia associated with cholinergic dysfunction, such as in Alzheimers disease (AD).

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Moreno-Rodriguez, M., Martinez-Gardeazabal, J., Bengoetxea de Tena, I., Llorente-Ovejero, A., Lombardero, L., Gonzalez de San Roman, E., Manuel, I., Gimenez-Llort, L., Rodriguez-Puertas, R.. 2024-03-12. Cortical lipids containing choline mediate cannabinoid-induced cognitive improvement. https://doi.org/10.1101/2024.03.07.583670

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