Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5739081 | Progress in Neurobiology | 2017 | 60 Pages |
Abstract
Despite efforts to understand the mechanism of neuronal cell death, finding effective therapies for neurodegenerative diseases is still a challenge. Cognitive deficits are often associated with neurodegenerative diseases. Remarkably, in the absence of consensus biomarkers, diagnosis of diseases such as Alzheimer's still relies on cognitive tests. Unfortunately, all efforts to translate findings in animal models to the patients have been unsuccessful. Alzheimer's disease may be addressed from two different points of view, neuroprotection or cognitive enhancement. Based on recent data, the mammalian target of rapamycin (mTOR) pathway arises as a versatile player whose modulation may impact on mechanisms of both neuroprotection and cognition. Whereas direct targeting of mTOR does not seem to constitute a convenient approach in drug discovery, its indirect modulation by other signaling pathways seems promising. In fact, G-protein-coupled receptors (GPCRs) remain the most common 'druggable' targets and as such pharmacological manipulation of GPCRs with selective ligands may modulate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and mTOR signaling pathways. Thus, GPCRs become important targets for potential drug treatments in different neurodegenerative disorders including, but not limited to, Alzheimer's disease. GPCR-mediated modulation of mTOR may take advantage of different GPCRs coupled to different G-dependent and G-independent signal transduction routes, of functional selectivity and/or of biased agonism. Signals mediated by GPCRs may act as coincidence detectors to achieve different benefits in different stages of the neurodegenerative disease.
Keywords
CREBPI3KTORTHCAβmTORCNTFERKSTMPP2AMAMTSCLTMCaMKIIGPCRsPKCNFTsRGS3xTgADL-LTPtetrahydrocannabinolGPR404E-BP1AGCMNKmTORC1SGK1PKCα4E-BP4E binding proteinPDK1RTKULK1PIP34E binding protein 1FIP200mTORC2PIP2S6KProtein kinase C αmSIN1mTOR complex 2PRAS40Atg13unc-51-like kinase 1mLST8BDNFCa2+/Calmodulin-dependent kinase IIcAMPeIFG protein-coupled receptorsIgf1MAPKMAPK/ERK kinasemTOR complex 1NFκBCyclic adenosine monophosphateamyloid-betaAktFingerAlzheimer’s diseaseParkinson’s diseaselong-term potentiationLTPPositron emission tomographyRTK, Receptor tyrosine kinaselong-term memoryshort-term memoryCNSRaptorRictorcentral nervous systemendoplasmic reticulumGAPEukaryotic Initiation FactorVascular endothelial growth factorVascular Endothelial Growth Factor (VEGF)insulin-like growth factor 1Brain-derived neurotrophic factorciliary neurotrophic factornuclear factor-κBphosphatase and tensin homologphosphatidylinositol-3,4,5-trisphosphatephosphatidylinositol 3 kinasephosphatidylinositol 4,5-biphosphateMEKHydrophobic motifneurofibrillary tanglesmammalian target of rapamycinrapamycin-insensitive companion of mTORphosphoinositide-dependent kinase 1PETribosomal protein S6 kinaseprotein phosphatase 2AGTPase-activating proteinregulatory-associated protein of mTORprotein kinase BProtein kinase Cmitogen-activated protein kinasePtenextracellular signal-regulated kinasesDEPTORAdenosine receptorcannabinoid receptor
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Authors
Rafael Franco, Eva MartÃnez-Pinilla, Gemma Navarro, Marta Zamarbide,