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dc.contributor.authorRuiz Pérez, Gonzalo
dc.contributor.authorRuiz de Martín Esteban, Samuel
dc.contributor.authorMarqués, Sharai
dc.contributor.authorAparicio, Noelia
dc.contributor.authorGrande Rodríguez, Mª Teresa 
dc.contributor.authorBenito Cuesta, Irene
dc.contributor.authorMartínez Relimpio, Ana María 
dc.contributor.authorArnanz, M. Andrea
dc.contributor.authorTolón, Rosa María 
dc.contributor.authorPosada Ayala, María
dc.contributor.authorCravatt, Benjamin F.
dc.contributor.authorEsteban, José A.
dc.contributor.authorRomero, Julián 
dc.contributor.authorPalenzuela Muñoz, Rocío 
dc.date.accessioned2022-02-21T10:12:19Z
dc.date.available2022-02-21T10:12:19Z
dc.date.issued2021
dc.identifier.issn1742-2094spa
dc.identifier.urihttp://hdl.handle.net/10641/2842
dc.description.abstractBackground: The complex pathophysiology of Alzheimer’s disease (AD) hampers the development of effective treatments. Attempts to prevent neurodegeneration in AD have failed so far, highlighting the need for further clarification of the underlying cellular and molecular mechanisms. Neuroinflammation seems to play a crucial role in disease progression, although its specific contribution to AD pathogenesis remains elusive. We have previously shown that the modulation of the endocannabinoid system (ECS) renders beneficial effects in a context of amyloidosis, which triggers neuroinflammation. In the 5xFAD model, the genetic inactivation of the enzyme that degrades anandamide (AEA), the fatty acid amide hydrolase (FAAH), was associated with a significant amelioration of the memory deficit. Methods: In this work, we use electrophysiology, flow cytometry and molecular analysis to evaluate the cellular and molecular mechanisms underlying the improvement associated to the increased endocannabinoid tone in the 5xFAD mouse− model. Results: We demonstrate that the chronic enhancement of the endocannabinoid tone rescues hippocampal synaptic plasticity in the 5xFAD mouse model. At the CA3–CA1 synapse, both basal synaptic transmission and longterm potentiation (LTP) of synaptic transmission are normalized upon FAAH genetic inactivation, in a CB1 receptor (CB1R)- and TRPV1 receptor-independent manner. Dendritic spine density in CA1 pyramidal neurons, which is notably decreased in 6-month-old 5xFAD animals, is also restored. Importantly, we reveal that the expression of microglial factors linked to phagocytic activity, such as TREM2 and CTSD, and other factors related to amyloid beta clearance and involved in neuron–glia crosstalk, such as complement component C3 and complement receptor C3AR, are specifically upregulated in 5xFAD/FAAH−/− animals. Conclusion: In summary, our findings support the therapeutic potential of modulating, rather than suppressing, neuroinflammation in Alzheimer’s disease. In our model, the long-term enhancement of the endocannabinoid tone triggered augmented microglial activation and amyloid beta phagocytosis, and a consequent reversal in the neuronal phenotype associated to the diseasespa
dc.language.isoengspa
dc.publisherJournal of Neuroinflammationspa
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 España*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/*
dc.titlePotentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer’s disease.spa
dc.typearticlespa
dc.description.versionpost-printspa
dc.rights.accessRightsopenAccessspa
dc.description.extent4206 KBspa
dc.identifier.doi10.1186/s12974-021-02276-yspa
dc.relation.publisherversionhttps://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02276-yspa


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