Elsevier

Progress in Neurobiology

Volumes 149–150, February–March 2017, Pages 21-38
Progress in Neurobiology

Review article
Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer’s disease

https://doi.org/10.1016/j.pneurobio.2017.01.004Get rights and content

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.

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.

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