Cannabinoids as a potent therapeutic target for Alzheimer's disease. (20th December 2022)

• Record Type: Journal Article
• Authors: Brugal, Gemma Navarro; Rivas‐Santisteban, Rafael; Marquez, Alejandro Lillo; Jové, Jaume Lillo; Franco, Rafael
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.066502
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: The NMDA receptor plays a central role in the CNS excitatory neurotransmission, being also a therapeutic target to combat AD. Receptor function deregulation is, at least in part, responsible for the progression of the disease. In this regard it would be interesting to discover membrane proteins capable of interacting with NMDA receptors, and being able to modulate their function to slow the onset of symptoms and the progressive neurodegeneration. Method: CB2 ‐NMDA complexes were identified in heterologous system by BRET technique and in primary cultures of control or APP Sw/Ind AD mice model by PLA. cAMP and MAPK signalling pathways were evaluated. Protein propagation was analyzed by microfluidic devices. Result: In a heterologous system we identified CB2 ‐NMDA complexes with a particular heteromer print consisting of impairment by cannabinoids of NMDA receptor function. The print was detected in activated primary microglia treated with lipopolysaccharide and interferon‐γ. CB2 R activation blunted NMDA receptor‐mediated signaling in primary hippocampal neurons from APPSw/Ind mice. Furthermore, imaging studies showed that primary cells (microglia or neurons) from APPSw/Ind mice displayed a marked overexpression of macromolecular CB2 ‐NMDA receptor complexes thus becoming a tool to modulate excessive glutamate input using cannabinoids. The expression of the CB2 ‐NMDA Hets increases in both microglia and neurons from the APP Sw/Ind transgenic mice, compared with levels in WT mice. Conclusion: The results indicate a negative cross‐talk in CB2 ‐NMDA complexes function, where cannabinoiods become an important neuroptotecting target by their own action and also by blocking NMDA signaling.