Browsing by Author "Cravatt, Benjamin F."
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Item Endocannabinoid regulation of amyloid-induced neuroinflammation(Neurobiology of Aging, 2015) Vázquez, Carmen; Tolón, Rosa María; Grande Rodríguez, Mª Teresa; Caraza, Marina; Moreno, Marta; Koester, Erin C.; Villaescusa, Borja; Ruiz Valdepeñas, Lourdes; Fernández Sánchez, Francisco Javier; Cravatt, Benjamin F.; Hillard, Cecilia J.; Romero, JuliánThe modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer’s disease (AD). We aimed to evaluate the effect of the pharmacological and genetic inhibiton of anandamide (AEA)-degrading enzyme in a mouse model of AD (5xFAD). Pharmacological inhibition of the fatty acid amide hydrolase (FAAH) had little impact on the expression of key enzymes and cytokines as well as on the cognitive impairment and plaque deposition and gliosis in 5xFAD mice. CB1 blockade exacerbated inflammation in this transgenic mouse model of AD. The genetic inactivation of FAAH led to increases in the expression of inflammatory cytokines. At the same time, FAAH-null 5xFAD mice exhibited a behavioral improvement in spatial memory that was independent of the level of anxiety and was not CB1-mediated. Finally, mice lacking FAAH showed diminished soluble amyloid levels, neuritic plaques and gliosis. These data reinforce the notion of a role for the endocannabinoid system in neuroinflammation and open new perspectives on the relevance of modulating endocannabinoid levels in the inflammed brain.Item Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer’s disease.(Journal of Neuroinflammation, 2021) Ruiz Pérez, Gonzalo; Ruiz de Martín Esteban, Samuel; Marqués, Sharai; Aparicio, Noelia; Grande Rodríguez, Mª Teresa; Benito Cuesta, Irene; Martínez Relimpio, Ana María; Arnanz, M. Andrea; Tolón, Rosa María; Posada Ayala, María; Cravatt, Benjamin F.; Esteban, José A.; Romero, Julián; Palenzuela Muñoz, RocíoBackground: 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 diseaseItem Role of interleukin 1-beta in the inflammatory response in a fatty acid amide hydrolase-knockout mouse model of Alzheimer’s disease.(Biochemical Pharmacology, 2018) Aparicio, Noelia; Grande Rodríguez, Mª Teresa; Ruiz de Martín Esteban, Samuel; López, Alicia; Ruiz Pérez, Gonzalo; Amores, Mario; Vázquez, Carmen; Martínez Relimpio, Ana María; Ruth Pazos, M.; Cravatt, Benjamin F.; Tolón, Rosa María; Romero, JuliánThe search for novel therapies for the treatment of Alzheimer’s disease is an urgent need, due to the current paucity of available pharmacological tools and the recent failures obtained in clinical trials. Among other strategies, the modulation of amyloid-triggered neuroinflammation by the endocannabinoid system seems of relevance. Previous data indicate that the enhancement of the endocannabinoid tone through the inhibition of the enzymes responsible for the degradation of their main endogenous ligands may render beneficial effects. Based on previously reported data, in which we described a paradoxical effect of the genetic deletion of the fatty acid amide hydrolase, we here aimed to expand our knowledge on the role of the endocannabinoid system in the context of Alzheimer’s disease. To that end, we inhibited the production of interleukin-1, one of the main inflammatory cytokines involved in the neuroinflammation triggered by amyloid peptides, in a transgenic mouse model of this disease by using minocycline, a drug known to impair the synthesis of this cytokine. Our data suggest that interleukin-1 may be instrumental in order to achieve the beneficial effects derived of fatty acid amide hydrolase genetic inactivation. This could be appreciated at the molecular (cytokine expression, amyloid production, plaque deposition) as well as behavioral levels (memory impairment). We here describe a previously unknown link between the endocannabinoid system and interleukin-1 in the context of Alzheimer’s disease that open new possibilities for the development of novel therapeutics.