Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer's disease. (February 2017)

• Record Type: Journal Article
• Authors: Franco, Rafael; Martínez-Pinilla, Eva; Navarro, Gemma; Zamarbide, Marta
• Is Part Of: Progress in neurobiology. Volume 149/150(2017)
• Page Start: 21
• Page End: 38
• Publication Date: 2017-02
• Subjects: AD Alzheimer's disease -- AGC protein kinase A/protein kinase G/protein kinase C -- Akt protein kinase B -- ATG13 autophagy-related gene 13 -- Aβ amyloid-beta -- BDNF brain-derived neurotrophic factor -- CaMKII Ca2+/calmodulin-dependent kinase II -- cAMP cyclic adenosine monophosphate -- CNS central nervous system -- CNTF ciliary neurotrophic factor -- CREB response element-binding protein -- Deptor DEP-domain-containing mTOR-interacting protein -- eIF eukaryotic initiation factor -- ER endoplasmic reticulum -- Erks or ERK1/2 extracellular signal-regulated kinases -- FINGER Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability -- FIP200 focal adhesion kinase family-interacting protein of 200 kDa -- FRAP1 FK506-binding protein 12-rapamycin-associated protein 1 -- GAP GTPase-activating protein -- GPCRs G protein-coupled receptors -- HM hydrophobic motif -- IGF1 insulin-like growth factor 1 -- L-LTP late-phase long-term potentiation -- LTM long-term memory -- LTP long-term potentiation -- MAM mitochondrial-associated ER membrane -- MAPK mitogen-activated protein kinase -- MEK MAPK/ERK kinase -- mLST8 mammalian lethal with Sec13 protein 8 -- MNK mitogen activated protein-interacting kinase -- mSIN1 mammalian stress-activated protein kinase interacting protein -- mTOR mechanistic TOR -- mTORC1 mTOR complex 1 -- mTORC2 mTOR complex 2 -- NFTs neurofibrillary tangles -- NFκB nuclear factor-κB -- PD Parkinson's disease -- PDK1 phosphoinositide-dependent kinase 1 -- PET positron emission tomography -- PI3K phosphatidylinositol 3 kinase -- PIP2 phosphatidylinositol 4, 5-biphosphate -- PIP3 phosphatidylinositol-3, 4, 5-trisphosphate -- PKC protein kinase C -- PKCα protein kinase C α -- PP2A protein phosphatase 2A -- PRAS40 proline rich Akt substrate 40 kDa -- Protor-1 protein observed with Rictor-1 -- PTEN phosphatase and tensin homolog -- Raptor regulatory-associated protein of mTOR -- RGS regulators of G protein-signaling -- Rictor rapamycin-insensitive companion of mTOR -- RTK receptor tyrosine kinase -- S6K ribosomal protein S6 kinase -- SGK1 serum and glucocorticoid-induced protein kinase 1 -- STM short-term memory -- THC tetrahydrocannabinol -- TOR mammalian target of rapamycin -- TSC heterodimeric tuberous sclerosis complex -- ULK1 unc-51-like kinase 1 -- VEGF vascular endothelial growth factor -- 3xTgAD triple-transgenic mouse model of AD -- 4E-BP1 4E binding protein 1 -- 4E-BP 4E binding protein; Alzheimer's disease -- GPR40 -- Cannabinoid receptor -- Adenosine receptor -- ERK -- mTOR; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2017.01.004
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: We present evidence, gathered over the last decade, concerning the potential of the mammalian target of rapamycin (mTOR) pathway as impacting in both neuroprotection and cognition. We state how mTOR and another key pathway in neural cells, the mitogen-activated protein (MAP) kinase, may be regulated via G-protein-coupled receptors (GPCRs). We also emphasize reasons why some GPCRs seem more appropiate than others as therapeutic targets to combat Alzheimer's disease. 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.