Review articlePotential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer’s disease
Introduction
Alzheimer's disease (AD) is a devastating, frequent and still incurable neurodegenerative disease, being the cerebral cortex and the hippocampus the main anatomical substrates of AD pathophysiology. AD is clinically featured by cognitive impairment and progressive memory loss. The AD brain is characterized by extracellular senile plaques, which contain amyloid-beta (Aβ) peptide deposits, and by intracellular neurofibrillary tangles (NFTs), which contain hyperphosphorylated microtubule-associated protein tau aggregates. Neuronal stress and neuronal circuit disruption culminates in neurodegeneration and brain atrophy (reviewed in Selkoe, 2001).
A first issue in AD is proper diagnosis. Because AD is multifactorial, symptoms may vary tremendously from person to person. In 2011, the National Institute on Aging developed a report with new guidelines for diagnosis (https://www.nia.nih.gov/research/dn/alzheimers-diagnostic-guidelines). It incorporated a substantial amount of new tests that look at different biomarkers to diagnose AD. Still now, definitive diagnosis of AD relies on post mortem analysis of the extent of plaque deposition in the brain.
Prescribed drugs do not prevent or slow down the progression of the disease and the improvement of day-life activities is modest. Regrettably, treatments start in late phases when it is doubtful that any therapy may prevent neurodegeneration or restore cognition.
Much of the research is currently focusing on amyloid and tau proteins, whose aberrant forms are one of the main AD features. Unfortunately, anti-amyloid approaches attempted to date have not been very successful due to side effects and poor clinical outcomes (Jia et al., 2014, Lannfelt et al., 2014). Over the last decade, more than 400 treatments were studied in clinical trials for AD. Even after showing potentially promising results in animal studies, they did not conclusively demonstrate any capacity to delay the progression of the disease in human trials (Cummings et al., 2014, Franco and Cedazo-Minguez, 2014, Mangialasche et al., 2010).
The study of AD has been greatly facilitated by the development of transgenic animal models. They have been instrumental in demonstrating that accumulation of AD-related proteins can cause learning and memory deficits prior to Aβ deposition and tangle formation in the hippocampus. Behavioral and synaptic plasticity deficits – primarily long term potentiation (LTP) impairment – have been shown in close temporal relation to intracellular Aβ immunoreactivity (Oddo et al., 2003). Ripoli et al., 2014 demonstrated that the intracellular accumulation of Aβ affects glutamatergic neurotransmission at both presynaptic and postsynaptic levels.
Collectively, a high amount of data suggests that, although the AD brain is characterized by the accumulation of Aβ plaques and tau in NFTs, other forms of these proteins may be important drivers of pathology (Cleary et al., 2005, Fá et al., 2016). For example, a recent study shows that soluble Aβ promotes a reduction in neuronal number and spine density, which are among the most significant AD hallmarks related with the cognitive function (Price et al., 2014, Tu et al., 2014). It is unlikely that a single factor or a single class of molecules is responsible for all synaptic alterations and morphological changes that occur in central nervous system (CNS) structures of AD patients. In this context, the regulatory role of neuromodulators acting on G protein-coupled receptors (GPCRs) acquires relevance, and suggest clinical implications.
Targeting GPCRs remains one of the most promising strategies to combat neurodegenerative diseases (Navarro et al., 2016). They are capable of sensing signals on the cell surface and convert them into short-term and/or long-term cell responses (Fernández-Fernández et al., 2015, Zhang and Stackman, 2015). Activation of GPCRs drives changes in gene transcription patterns that are involved in memory formation and long-term memory (LTM) consolidation (Kemmel et al., 2010). Signaling by GPCRs is also involved in short-term memory (STM) mechanisms via post-translational effects occurring after protein phosphorylation (Raote et al., 2007). These responses are mainly mediated by changes in the activation pattern of the extracellular signal-regulated kinases (ERKs or ERK1/2) that in turn result in the repression or induction of the expression of cell/tissue-specific genes. In fact, GPCRs may act as coincidence detectors and as signal integrators.
GPCRs play a fundamental role in regulating various physiological and pathophysiological processes and are regarded as potential therapeutic targets in many diseases (Zalewska et al., 2014), with approximately 50% of marketed drugs targeting GPCRs (Heng et al., 2014). Recently, we have shown that a free fatty acid GPCR known as GPR40, previously studied in the pancreas, is also expressed in the CNS where it has important regulatory functions. GPR40 directs the activation of the ERKs by the mitogen-activated protein kinase (MAPK) pathway, leading to the phosphorylation of the cAMP (cyclic adenosine monophosphate) response element-binding protein (CREB), whose role in neuronal plasticity and LTM has been widely demonstrated (Zamarbide et al., 2014). GPCRs for structurally different hormones/neuromodulators, from endocannabinoids to adenosine, signal via the ERK1/2 MAPK pathway and are expressed in CNS neural cells (Andradas et al., 2011, Angulo et al., 2003, Balenga et al., 2014, Henstridge et al., 2010, Martínez-Pinilla et al., 2014, Pérez-Gómez et al., 2012).
ERKs are expressed in different cell types and subcellular localizations, where they allow cross-talk between a wide array of signals and signal transduction pathways. It has been suggested that ERKs may act as detectors of signals arriving at the same time from two separate upstream pathways (Geetha et al., 2011). This family of kinases in neurons do mediate synaptic events involved in learning and needed for the formation of memory traces (Chang and Karin, 2001, Hullinger et al., 2015). ERKs appear to be salient in LTM and in the molecular mechanisms underlying STM formation in the hippocampus. ERKs involvement in regulating neuronal plasticity has two sides: i) regulation of protein synthesis and ii) regulation of protein phosphorylation in dendrites (Allen et al., 2014, Borroto-Escuela et al., 2011). Interestingly, different studies report the involvement of ERKs in the activation of downstream cytoplasmic proteins such as mammalian target of rapamycin (mTOR) (Wang et al., 2014a, Wang et al., 2014b, Wang et al., 2014c). The number of reports linking GPCR-mediated modulation of mTOR signaling in brain is still low (Giovannini et al., 2015, Ma et al., 2010, Peart et al., 2014). The mTOR pathway regulates homeostasis by directly influencing gene transcription, protein synthesis and cell autophagy (Laplante and Sabatini, 2009). Those roles connect this pathway with AD and other neurodegenerative diseases. Noteworthy, hippocampal slices and primary cultures from transgenic models of AD, and even hippocampal slices from wild-type mice treated with amyloid Aβ1-42 peptide, display reduced mTOR signaling (Ma et al., 2010).
In this review, we address the links between GPCR activation, ERK signaling, and the mTOR pathway, as well as the potential of GPCRs for neuromodulators (such as cannabinoids or adenosine) to be targets to prevent cognitive decline via the mTOR pathway.
Section snippets
Description and function
GPCRs belong to the most populated protein family in the human genome. The estimated number of GPCRs is in between 700 and 1000, and they are subdivided into three main subfamilies A, B and C that share the capacity to interact with heterotrimeric Gαβγ proteins (Pierce et al., 2002). Common features of these integral membrane proteins include a seven-transmembrane domain, an extracellular N-terminal domain and an intracellular C-terminal domain (Fig. 1). Another relevant characteristic is their
Selective GPCR-mediated activation of ERK1/2
After the first successes on targeting GPCRs using β-adrenergic receptor blockers and antihistamines (Pearlman, 1976, Theilen and Wilson, 1968, Williams et al., 1975), the potential of GPCR-based drug discovery has been substantiated by screening cAMP or calcium responses. More recently, the interest in longer-term responses to GPCR signaling has grown, especially given the possibility to regulate changes in cellular plasticity through GPCR-mediated transcriptomic signatures. Activation of
mTOR, autophagy and Alzheimer’s disease
In the early 1990s, seminal studies in yeast and mammalian models identified a large 289 kDa protein as a rapamycin cell target; accordingly, it was named the mammalian target of rapamycin (TOR) but it is now known as mechanistic TOR (mTOR) (reviewed in Guertin and Sabatini, 2007). mTOR, an atypical member of the PI3K-related serine/threonine kinase family, previously known as FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1) (www.genecards.org), is ubiquitously expressed in many
GPCRs as targets to regulate mTOR signaling
Inhibitors of mTOR signaling may be of therapeutic interest to combat AD (Cai et al., 2015, Maiese, 2014, Wang et al., 2014a, Wang et al., 2014b, Wang et al., 2014c). A successful approach in the 3×Tg-AD transgenic model consists of providing an inhibitor of the kinase activity of protooncogene Pim1 that may reduce the level of PRAS40 phosphorylation, which is elevated in the brain from AD patients and correlates with neural pathologies and cognitive deficits (Velazquez et al., 2016). However,
Future directions
Evidence that the mTOR signaling pathway is impaired in the brain of AD patients is now overwhelming. Although such disbalance may be cause or consequence of the disease, it is becoming clear that interventions aimed at regulating the pathway may be useful to combat AD. Interventions that directly target mTOR components have technical difficulties derived inter alia from the complexity of the pathway and the variety of mTOR1/mTOR2 protein components. Direct targeting of mTOR looks promising in
Acknowledgement
Authors thank Dr. Adam W. Oaks for inspiring discussions and help in editing the manuscript.
References (264)
- et al.
Deficiency of polycystic kidney disease-1 gene (PKD1) expression increases A(3) adenosine receptors in human renal cells: implications for cAMP-dependent signalling and proliferation of PKD1-mutated cystic cells
Biochim. Biophys. Acta
(2009) - et al.
Aversive experiences are associated with a rapid and transient activation of ERKs in the rat hippocampus
Neurobiol. Learn. Mem.
(2002) - et al.
Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer’s disease
Am. J. Pathol.
(2003) - et al.
Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson’s disease
Pharmacol. Ther.
(2011) - et al.
Nicotinic acetylcholine receptors sensitize a MAPK-linked toxicity pathway on prolonged exposure to β-Amyloid
J. Biol. Chem.
(2015) - et al.
The potential role of adenosine in the pathophysiology of the insulin resistance syndrome
Atherosclerosis
(2001) - et al.
mTOR signaling in the hippocampus is necessary for memory formation
Neurobiol. Learn. Mem.
(2007) Autophagy: a cell repair mechanism that retards ageing and age-associated diseases and can be intensified pharmacologically
Mol. Aspects Med.
(2006)- et al.
The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids
J. Biol. Chem.
(2003) - et al.
Regulation of Ras-mediated signalling: more than one way to skin a cat
Trends Biochem. Sci.
(1995)
Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism
J. Biol. Chem.
Cannabinoid receptors CB1 and CB2 form functional heteromers in brain
J. Biol. Chem.
Adenosine receptor control of cognition in normal and disease
Int. Rev. Neurobiol.
Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials
Lancet (London, England)
Seven transmembrane-spanning receptors for free fatty acids as therapeutic targets for diabetes mellitus: pharmacological, phylogenetic, and drug discovery aspects
J. Biol. Chem.
The soluble extracellular fragment of neuroligin-1 targets Aβ oligomers to the postsynaptic region of excitatory synapses
Biochem. Biophys. Res. Commun.
Communications: a requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation a requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation *
J. Biol. Chem.
Alternatively activated microglia and macrophages in the central nervous system
Prog. Neurobiol.
mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s
Curr. Biol.
ULK1{middle dot}ATG13{middle dot}FIP200 complex mediates mTOR signaling and is essential for autophagy
J. Biol. Chem.
Synaptic plasticity alterations associated with memory impairment induced by deletion of CB2 cannabinoid receptors
Neuropharmacology
Signal integration and coincidence detection in the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) cascade: concomitant activation of receptor tyrosine kinases and of LRP-1 leads to sustained ERK phosphorylation via down-regu
J. Biol. Chem.
Effects of novelty and habituation on acetylcholine, GABA, and glutamate release from the frontal cortex and hippocampus of freely moving rats
Neuroscience
The integrated role of ACh, ERK and mTOR in the mechanisms of hippocampal inhibitory avoidance memory
Neurobiol. Learn. Membr.
Multiple site acetylation of rictor stimulates mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of Akt protein
J. Biol. Chem.
Defining the role of mTOR in cancer
Cancer Cell
Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1
Dev. Cell
Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action
Cell
The role of PI3 K/Akt/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration
Cell. Signal.
Group 5 metabotropic glutamate receptors: role in modulating cortical activity and relevance to cognition
Eur. J. Pharmacol.
Environmental enrichment improves learning and memory and long-term potentiation in young adult rats through a mechanism requiring mGluR5 signaling and sustained activation of p70s6k
Neurobiol. Learn. Mem.
The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK
J. Neurochem.
The MAP kinase cascade. Discovery of a new signal transduction pathway
Mol. Cell. Biochem.
Nucleolar integrity is required for the maintenance of long-term synaptic plasticity
PLoS One
The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK
Oncogene
A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation
Brain Pathol.
Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic
Front. Pharmacol.
Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling
Br. J. Pharmacol.
Aberrant insulin signaling in Alzheimer’s disease: current knowledge
Front. Neurosci.
MAPK recruitment by beta-amyloid in organotypic hippocampal slice cultures depends on physical state and exposure time
J. Neurochem.
Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains
J. Neurosci.
associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology
Proc. Natl. Acad. Sci. U. S. A.
The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events
Mol. Neurodegener.
Learning decreases a *56 and tau pathology and ameliorates behavioral decline in 3xTg-AD mice
J. Neurosci.
Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors
Proc. Natl. Acad. Sci. U. S. A.
Autophagy flux in CA1 neurons of Alzheimer hippocampus: increased induction overburdens failing lysosomes to propel neuritic dystrophy
Autophagy
Moonlighting characteristics of G protein-coupled receptors: focus on receptor heteromers and relevance for neurodegeneration
IUBMB Life
Fighting neurodegeneration with rapamycin: mechanistic insights
Nat. Rev. Neurosci.
Scientists in the dark after French clinical trial proves fatal
Nature
mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies
Aging Cell
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