The Role of Gpcrs in Neurodegenerative Diseases

Available online at www.sciencedirect.com

ScienceDirect

The role of GPCRs in neurodegenerative diseases:

avenues for therapeutic intervention

1 2 1,2,3,4

Yunhong Huang , Nicholas Todd and Amantha Thathiah

Neurodegenerative diseases represent a large group of cognitive function, memory loss, and negative personality

neurological disorders with heterogeneous clinical and changes [3–5]. The pathological features of AD include

pathological proﬁles. The majority of current therapeutic the accumulation of amyloid b (Ab) in amyloid plaques

strategies provide temporary symptomatic relief but do not and hyperphosphorylated aggregates of the microtubule-

target the underlying disease pathobiology and thus do not associated protein tau in neuroﬁbrillary tangles, which are

affect disease progression. G protein-coupled receptors ﬁrst detected in the frontal and temporal lobes and then

(GPCRs) are among the most successful targets for therapeutic slowly progress to the other areas of the neocortex [5].

development of central nervous system (CNS) disorders. Many VaD is the second most common cause of dementia with a

current clinical therapeutic agents act by targeting this class of variable age of onset. VaD patients display a disturbance in

receptors and downstream signaling pathways. Here, we frontal executive function [6] and multiple cerebrovascular

review evidence that perturbation of GPCR function pathologies, including vessel occlusion, arteriosclerosis,

contributes to the pathophysiology of various hypertensive, aneurysms, and various forms of arteritis

neurodegenerative diseases, including Alzheimer’s disease, [7 ,8 ]. Frontotemporal dementia (FTD) is a major cause

Frontotemporal dementia, Vascular dementia, Parkinson’s of dementia in persons under the age of 65 [9] and

disease, and Huntington’s disease. is characterized by neuropsychiatric symptoms and

behavioral, motor, and cognitive impairments [10]. The

Addresses pathological features of FTD include the abnormal depo-

Department of Neurobiology, University of Pittsburgh School of sition of three major proteins—tau, transactive response

Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA DNA-binding protein 43 (TDP-43), and fused in sarcoma

University of Pittsburgh Brain Institute, University of Pittsburgh School

(FUS) protein [10] in brain regions such as the hippocam-

of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA

3 pus, frontal cortex, and striatum [11].

Pittsburgh Institute for Neurodegenerative Diseases, University of

Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh,

PA 15213, USA Parkinson’s disease (PD) is second most common neuro-

KU Leuven Center for Human Genetics, Leuven 3000, Belgium

degenerative disease, with an average onset of 50–60

years of age [12]. PD is characterized by motor and

Corresponding author: Thathiah, Amantha ([email protected])

non-motor symptoms. The prominent motor symptoms

in PD patients include bradykinesia, rigidity, tremor, and

Current Opinion in Pharmacology 2017, 32:96–110 gait disorders [13]. Non-motor clinical features include

This review comes from a themed issue on Neurosciences cognitive impairment and neuropsychiatric symptoms

[13]. The pathological features of PD include deposi-

Edited by David Chatenet and Terence E. He´ bert

tion of Lewy bodies and abnormal aggregates of the

For a complete overview see the Issue and the Editorial

a-synuclein protein in several brain regions, such as the

Available online 10th March 2017

substantia nigra and temporal cortex, and the loss of

http://dx.doi.org/10.1016/j.coph.2017.02.001 dopaminergic neurons in the substantia nigra [13].

Similar to PD, Huntington’s disease (HD) patients suf-

fer from motor and non-motor symptoms. HD patients

suffer from motor symptoms such as chorea, bradykine-

sia, impaired coordination, and rigidity and non-motor

symptoms such as depression and slowed cognitive

Introduction function [14]. HD is caused by a CAG trinucleotide

Neurodegenerative diseases are a major cause of disabil- repeat expansion in the Huntingtin (Htt) gene [14].

ity and premature death among the elderly people world- The CAG repeats vary from 6 to 35 nucleotides in

wide [1]. Alzheimer’s disease (AD), Vascular dementia unaffected individuals. A longer series of CAG repeats

(VaD), Frontotemporal dementia (FTD), Parkinson’s (>36) are present in HD patients and inversely correlate

disease (PD), and Huntington’s disease (HD) are the with the age of onset [15]. The deposition of HTT is

among the most prevalent neurodegenerative diseases most frequent in the cerebral cortex, and much less in

[2]. AD is the most common neurodegenerative disease other brain regions such as striatum, hippocampus, and

and the predominant cause of dementia in the population cerebellum [16]. Collectively, AD, VaD, FTD, PD,

over 65 years of age. AD is characterized by impaired and HD are neurodegenerative diseases with clinical

Current Opinion in Pharmacology 2017, 32:96–110 www.sciencedirect.com

Role of GPCRs in neurodegenerative diseases Huang, Todd and Thathiah 97

features that include cognitive deﬁcits, motor impair- function [28]. Acetylcholinesterase inhibitors and mem-

ments, and neuropsychiatric symptoms. antine are the only available symptomatic treatments that

slow the decline in cognitive function in individuals with

G protein-coupled receptors (GPCRs) have been impli- AD [24]. In this section, we highlight some of the GPCRs

cated in the pathogenesis of several neurodegenerative that have been rigorously evaluated in the modulation

diseases [17,18], including AD, VaD, FTD, PD, and HD. of cognitive function in AD mouse models in recent

GPCRs are the largest family of membrane proteins [19]. literature. Additional GPCRs that have been implicated

Over 370 non-sensory GPCRs have been identiﬁed of in the pathophysiology of AD have been included in

which more than 90% are expressed in the brain, where Table 1.

they play important roles in mood, appetite, pain, vision,

immune regulation, cognition, and synaptic transmission Glutamate receptors mediate most of the excitatory neu-

[20]. GPCR ligands include a variety of molecules such as rotransmission in the mammalian brain [29]. The meta-

photons, ions, biogenic amines, peptide, hormones, botropic glutamate receptor (mGluR) family mediate

growth factors, and lipids [21]. Consequently, GPCRs glutamate neurotransmission. MGluR5 has been shown

represent the most common target for therapeutic drugs. to be involved in cognitive function and Ab generation.

Here, we mainly focus on the GPCRs that have been Genetic deletion of mGluR5 has been shown to alleviate

reported in the past 5 years and several well-documented cognitive impairment and Ab production in an APPswe/

GPCRs that have been reported to be involved in the PSEN1DE9 AD mouse model, which overexpresses

pathophysiology of the neurodegenerative diseases human APP harboring the Swedish mutation and human

mentioned above. We review the correlation between presenilin 1 lacking exon 9 [30]. Interestingly, pharmaco-

changes in GPCR expression and/or activity with the logical inhibition of mGluR5 with 3-[(2-methyl-1,3-thia-

neuropathological hallmarks and clinical symptoms zol-4-yl)ethynyl]-pyridine (MTEP), an antagonist, has

of these neurodegenerative diseases and discuss the also been shown to alleviate the cognitive deﬁcits in

currently available therapeutic strategies targeting the the same AD mouse model [31]. Similarly, treatment

GPCRs discussed in the text. with the mGluR5 negative allosteric modulator 2-

chloro-4-((2,5-dimethyl-1-(4-(triﬂuoromethoxy)phenyl)-

Alzheimer’s disease 1H-imidazol-4-yl)ethynyl) pyridine (CTEP) alleviates

GPCRs and cognitive deﬁcits in AD the cognitive deﬁcits and reduces the amyloid plaque

AD leads to signiﬁcant degeneration of various brain burden in two AD mouse models [32]. These studies

regions and the alteration of multiple neurochemical suggest that allosteric modulators of mGluR5 may be an

pathways. Magnetic resonance imaging (MRI) studies effective therapeutic strategy for some AD cases.

have shown that a reduction in the volume of the hippo-

campus and entorhinal cortex, which are affected early in Extensive serotonergic denervation of the neocortex and

disease progression [5,22], and cortical thickness of the hippocampus has been observed in AD patients. Reduc-

medial temporal, inferior temporal, temporal pole, angu- tion in 5-hydroxytryptamine (5-HT, serotonin) and 5-

lar gyrus, superior parietal, superior frontal, and inferior HT1A, 5-HT2A, 5-HT4, and 5-HT6 receptor levels have

frontal cortex correlate with the cognitive deﬁcits been reported in the hippocampus and/or prefrontal

observed in AD patients [3] (Figure 1a). Furthermore, cortex of AD patients. In rodent models, activation of

changes in multiple neurochemical pathways, including 5-HT2A and 5-HT4 receptors leads to an improvement in

the acetylcholine, serotonin, adenosine pathways have hippocampal-dependent learning and memory [33,34] via

been shown to be involved in the cognitive impairments G protein- or b-arrestin-dependent activation of extracel-

observed in AD. lular signal-regulated kinase (ERK) [35,36]. In contrast,

antagonism of the 5-HT1A and the least studied 5-HT5A

Currently, there is no effective treatment for AD. Levels receptors has been shown to ameliorate the memory

of acetylcholine are reduced in the brains of AD patients deﬁcits in a rat AD model [37,38], possibly through an

[23]. As such, acetylcholinesterase inhibitors have been inhibition of Gi signaling and activation of protein kinase

shown to temporarily ameliorate disease symptoms [24] A (PKA), which leads to the activation of the NMDA

by decreasing acetylcholine breakdown, which results in receptor [39,40]. Interestingly, both 5-HT6 receptor ago-

an increase in cholinergic neurotransmission and a mild nists and antagonists enhance learning and memory [41]

improvement in cognitive function. Excitotoxicity due through potentially different mechanisms of action. Acti-

to overstimulation of glutamatergic neurotransmission vation of the 5-HT6 receptor has been shown to stimulate

[25] is also associated with the pathophysiology of AD Gs protein-dependent brain-derived neurotrophic factor

[26]. Memantine is an N-methyl-D-aspartate (NMDA) (BDNF) mRNA expression and Fyn kinase-dependent

receptor antagonist that inhibits NMDA receptor-medi- activation of ERK1/2 in wild-type rats [42]. Both BDNF

ated calcium inﬂux into neurons [27] and protects exces- and ERK1/2 have been shown to be associated with

sive glutamate-induced neuronal death and excitotoxicity cognitive function [43,44]. In contrast, 5-HT6 receptor

[26], providing temporary improvement in cognitive antagonists have been shown to stimulate glutamate and

www.sciencedirect.com Current Opinion in Pharmacology 2017, 32:96–110 98 Neurosciences

Figure 1

(a) Alzheimer’s Disease PR IPL

MTG EC HP ITG TP H P

(b) Frontotemporal Dementia

S ACC STG MPC

A OFC MTG

DPC DPC

HP ITG MTG

Current Opinion in Pharmacology

Schematic representation of the association between brain atrophy and the clinical symptoms observed in Alzheimer’s disease, Frontotemporal

dementia, and Vascular dementia. Blue indicates brain regions that undergo atrophy and are associated with cognitive deficits. Green indicates

Current Opinion in Pharmacology 2017, 32:96–110 www.sciencedirect.com

Role of GPCRs in neurodegenerative diseases Huang, Todd and Thathiah 99

acetylcholine release in rat brains, which has been shown of Crhr1 in the PSAPP AD mouse model, which over-

to improve scopolamine- and MK-801-induced deﬁcits in express a chimeric mouse/human APP gene with human

associative learning [42]. These studies support the APP Swedish mutation and human presenilin 1 lacking

potential beneﬁt of selective modulation of the 5-HT exon 9, leads to a reduction in amyloid pathology [59 ].

receptor subtypes for AD therapy. Pharmacological studies in the Tg2576 AD mouse model,

which overexpresses human APP with the Swedish muta-

Expression of the adenosine A1 and A2A receptors (A1R tion, with the CRHR1 antagonist antalarmin in acutely (7-

and A2AR) has been reported to be elevated in the frontal days) or in chronically (9-months) stressed mice reduces

cortex of the human AD brain [45]. Caffeine, a nonselec- Ab production and involves the Gs signaling pathway

tive AR inhibitor, has been shown to enhance memory [60]; however, pre-treatment with antalarmin failed to

consolidation in humans [46] and reduce Ab levels and inhibit an increase in Ab levels in acutely (3-hours)

improve cognitive function in an AD mouse model [47]. stressed wild-type mice. In vitro cell-free g-secretase

Similarly, caffeine and the A2AR antagonist SCH58261 activity assays with the CRHR1 antagonists astressin,

has been shown to be protective against Ab-induced antalarmin, and NBI-27914 have been shown to modulate

cognitive impairment [48]. Interestingly, conditional Ab generation in the absence of CRHR1, suggesting that

deletion of astrocytic A2ARs has been shown to enhance the compounds tested may have CRHR1-independent

alleviate the memory deﬁcits in AD transgenic mice effects on the modulation of g-secretase activity [57 ].

through Gs-coupled signaling [49 ], whereas activation Treatment of wild-type mice with the CRHR1 antagonist

of the Gi-coupled A1R and inhibition of PKA has been antalarmin reduces depression-like behaviors, whereas

shown enhance long-term depression (LTD) [50]. These genetic deﬁciency of Crhr2 leads to an increase in depres-

studies potentially suggest that activation of Gs-coupled sion-like behaviors [61]. Although both receptors have

receptors, such as the A2AR, which activates PKA, may considerable sequence similarity, the two receptors have

suppress LTD and promote long-term plasticity (LTP), different expression patterns in the brain and afﬁnities for

whereas Gi-coupled receptors, such as the A1R may be CRH [62]. Interestingly, CRHR1 is more abundantly

involved in the induction of LTD. expressed in the pituitary gland, and atrophy of this

region is associated with the neuropsychiatric symptoms

In addition to GPCRs with identiﬁed ligands, the orphan in AD [63]. The in vivo studies suggest that a highly

GPCR GPR3 has been shown to modulate Ab generation selective antagonist speciﬁc for CRHR1 may be beneﬁ-

and cognitive function in vivo. Levels of GPR3 are cial for the symptoms of depression in AD; however,

elevated in the human AD brain [51,52]. Genetic deletion careful monitoring of Ab levels would also be necessary

of Gpr3 has been shown to alleviate the learning and to fully assess the therapeutic potential.

memory deﬁcits in an AD mouse model and reduce

amyloid pathology in four AD mouse models [53 ].

The GPR3-mediated effect on amyloid pathology Frontotemporal dementia

involves b-arrestin recruitment, independently of Gs- FTD is a heterogeneous neurodegenerative disease

coupling [51]. A more comprehensive discussion on the caused by degeneration and atrophy of the frontal and

GPCRs involved in the pathogenesis of AD is the subject temporal lobes. In general, FTD encompasses a wide

of recent reviews [54,55]. Together with the GPCRs such range of neuropathologies associated with mutations in

as 5-HT receptors, adenosine receptors that are involved several genes, including tau, TDP-43, and FUS, which

in affected neurochemical pathways in AD suggest viable leads to deterioration in behavior, personality, and motor

therapeutic avenues for the treatment of cognitive deﬁcits functions [10]. MRI and single-photon emission comput-

in AD. erized tomography (SPECT) reveal abnormalities and

atrophy in the frontal and temporal lobes of FTD

patients. Further post-mortem examination of FTD

GPCRs and neuropsychiatric symptoms in AD patient brains shows additional degeneration of the stria-

The corticotrophin-releasing hormone (CRH) receptor tum [64] (Figure 1b). FTD patients present with a variety

1 and 2 (CRHR1 and CRHR2) are GPCRs associated of neuropsychiatric, behavioral, motor, and cognitive

with depression [56,57 ]. Interestingly, a greater density impairments [64,65] including decline in social skills,

of amyloid plaques has been observed in the hippocam- depression, compulsive behavior, agitation, bradykinesia,

pus of AD patients with a previous history of major and/or apathy. Symptom heterogeneity has led to multi-

depression [58]. Reports also show that genetic deletion ple diagnostic clinical categories such as behavioral

(Figure 1 Legend Continued) brain regions that undergo atrophy and are associated with neuropsychiatric symptoms. Orange indicates brain

regions that undergo atrophy and are associated with motor impairments. Abbreviations for the indicated brain regions include: amygdala (A),

anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DPC), entorhinal cortex (EC), hypothalamus (H), hippocampus (HP), inferior parietal

lobule (IPL), inferior temporal gyrus (ITG), medial prefrontal cortex (MPC), medial temporal gyrus (MTG), orbitofrontal cortex (OFC), pituitary (P),

posterior cingulate (PC), precuneus (PR), striatum (S), superior temporal gyrus (STG), and temporal pole (TP).

www.sciencedirect.com Current Opinion in Pharmacology 2017, 32:96–110 100 Neurosciences ] ] ] ] ] ] ] 135,155 135 ] 136 141–143 144,145,151,152 154 137,140 137 R[ 2A A D1R [ M4R [ s Motor impairments a ] a ] ein-coupled receptor 52; GPR55, G 117 118 R, 5-hydroxytryptamine receptor 4; 5- 4 ] CB1R [ ] GPR52 [ ne receptor M4; mGluR2, metabotropic glutamate R, cysteinyl leukotriene receptor 1; D1R, dopamine 1 a ] ] D1R [ ] mGluR5 [ 157,158 ] D2R [ ] D2R [ ] mGluR2 [ 129,131 130 , sphingosine 1-phosphate receptor. 1 131 127 13 122 123 receptor; BAI1, brain-speciﬁc angiogenesis inhibitor 1; CB1R, R[ 2A 2A mGluR4 [ M4R [ ] GPR37] [ GPR55 [ ,153 ,153 ]A ] D1R [ ] M1R [ 101 101 R, adenosine A 106 106 ] D2R [ 2A R1 [ R2 [ R[ R[ R, 5-hydroxytryptamine receptor 2C; 5-HT B B 94,95 98 1A 2A 2C 5-HT 5-HT D1R [ GABA GABA M1R [ receptor; A a a 1 ] ] 10,86,87,150 10,86,87,150 R, adenosine A 1 -Aminobutyric acid B receptor; GIPR, glucose-dependent insulinotropic polypeptide receptor; GPR3, G protein- D1R [ D2R [ g R, B a a ] R, 5-hydroxytryptamine receptor 2A; 5-HT ] a a 2A ] ] a 89 73,74 72–74 ] 79 71 R[ R[ R[ 1A 2A 2C 5-HT 5-HT R, 5-hydroxytryptamine receptor 6; A 6 ] 5-HT a a ] ] 149 61 61 R[ 2A R, 5-hydroxytryptamine receptor 1A; 5-HT CRHR1 [ 1A 5-HT a ] ] ] a a a ]] 5-HT ] mGluR5 [ ] ] ] ] ]] CRHR2 [ OXTR [ a a a ] 159 161 ] ] 37 34 38 ] ] ] 30 33 41 163 164 ] R[ R[ 53 R[ R[ R[ 162 167 1 48,49 160 156 B 166 165 R[ R[ [ 48 1A 2A 4 5A 6 R, 5-hydroxytryptamine receptor 5A; 5-HT 1 R[ 5A R[ Studies which were not conducted in animal disease models. 1 2A

A BAI1 [ 5-HT 5-HT HT D1 receptor; D2R, dopamine D2 receptor; DOR, delta-opioid receptor; GABA 5-HT cannabinoid type 1 receptor; CRHR1, corticotrophin-releasing hormone receptor 1; CRHR2, corticotrophin-releasing hormone receptor 2; CysLT 5-HT CysLT coupled receptor 3; GPR30, G protein-coupled receptor 30;receptor GPR37, 2; G mGluR4, protein-coupled metabotropic receptor glutamate 37; receptor GPR48, 4; G mGluR5, protein-coupled metabotropic receptor glutamate 48; receptor GPR52, 5; G OXTR, prot oxytocin receptor; S1P protein-coupled receptor 55; M1R, muscarinic acetylcholine receptor M1; M3R, muscarinic acetylcholine receptor M3; M4R, muscarinic acetylcholi M3R [ GPR30 [ GABA DOR [ Abbreviations: Table 1 GPCRs that have been studied in humansAD and/or animal models Cognitive deficits Neuropsychiatric5-HT symptoms Neuropsychiatric symptoms Motor impairments Cognitive deficits Motor impairments Cognitive deficit GIPR [ GPR3 [ GPR48 [ M1R [ mGluR5 [ S1P FTDa VaD PD HD A

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Role of GPCRs in neurodegenerative diseases Huang, Todd and Thathiah 101

variant FTD (bvFTD), primary progressive aphasia cortex and isocortical brain regions of bvFTD patients,

(PPA), semantic dementia (SD), and FTD with parkin- which may precede the neurodegeneration observed in

sonism-17 (FTDP-17) [10]. FTD variants affect both select frontotemporal brain regions. Electrophysiology

distinct and overlapping brain regions and multiple neu- and behavioral studies suggest that mGluR5 activation

rochemical pathways, which poses a signiﬁcant challenge enhances NMDA receptor function, whereas mGluR5

for studying and treating the disease. Here, we discuss the inhibition exacerbates the effects of NMDA receptor

GPCRs that are the most prominent candidates for ther- blockade [80,81]. These studies suggest that mGluR5

apeutic treatment of the neuropsychiatric and motor may be in involved in reduced NMDA receptor neuro-

impairments in FTD. A more comprehensive list of transmission. Interestingly, mGluR5 has also been shown

the GPCRs involved in FTD can be found in Table 1. to play a role in Ab generation, memory, locomotor

function, and anxiety in an AD mouse model, indicating

GPCRs and neuropsychiatric symptoms in FTD the multiple functions of the receptor [30].

Deﬁcits in emotion recognition skills are thought to

contribute to deﬁcits in empathy and inappropriate social

behavior in FTD. Several studies suggest that the neuro- GPCRs and motor impairments in FTD

peptide oxytocin is an important mediator of social behav- The dopamine D1 and D2 receptors (D1R and D2R)

ior and neuropsychiatric behaviors in patients with FTD have been reported to play an important role in FTD.

[66]. In mammals, oxytocin is primarily produced within Both the D1R and D2R are most abundantly expressed in

the hypothalamic brain regions and is shuttled to the the striatum [82]. Because of disease heterogeneity, both

pituitary for systemic release or projected to various brain DR antagonists (antipsychotics) and agonists, which pre-

regions for paracrine signaling of the oxytocin receptor dominantly target the D2R, have been used to treat FTD.

(OXTR) in brain regions such as the amygdala and Clinically, DR antagonists are used to treat behavioral

anterior cingulate cortex, which have been implicated symptoms such as agitation and disinhibition, and DR

in the pathophysiology of FTD [67]. agonists are used to treat motor symptoms such as

rigidity and bradykinesia in bvFTD and FTDP-17,

Oxytocin administration has been shown to potentially respectively [10]. Typical antipsychotics such as halo-

improve social interactions [67] and facilitate the devel- peridol and ﬂuphenazine are not commonly used to treat

opment of GABAergic synapses, which inhibit signals FTD patients due to neuroleptic side-effects associated

that lead to fear and anxiety [68–70]. Interestingly, intra- with the high D2R afﬁnity [83]. In contrast, antipsycho-

nasal administration of oxytocin to FTD patients leads to tics such as olanzapine, quetiapine, and risperidone also

improved social interactions, namely patient–caregiver have a high afﬁnity for the D2R, but rapidly dissociate,

interactions [71]. resulting in fewer side effects [84]. Dopamine dysfunc-

tion has also been reported to be involved in behavioral

Levels of the 5-HT1A and 5-HT2A receptors are reduced deﬁcits in HD (see below); however, decreased D2R

in the anterior cingulate cortex [72] and orbitofrontal and levels has been reported to be the cause of these impair-

medial prefrontal cortex of FTD patients [73,74] and the ments [85].

frontal and temporal cortex of bvFTD patients [72–74].

Clinically, selective serotonin reuptake inhibitors (SSRIs) FTDP-17 patients who experience rigidity and brady-

such as ﬂuoxetine, ﬂuvoxamine, and sertraline, which kinesia primarily display a decrease in presynaptic dopa-

increase 5-HT levels by blocking 5-HT reuptake, have minergic nerve terminals and postsynaptic D2R binding

been used to provide symptomatic relief for depression in the striatum. Consequently, FTDP-17 patients are

and repetitive or compulsive behaviors observed in currently treated with DR agonists such as carbidopa

patients with multiple variants of FTD [75]. Interest- and levodopa, which have been approved for the treat-

ingly, lower levels of the 5-HT1A and 5-HT2A receptors in ment of PD [10,86,87] despite potential exacerbation of

the hippocampus and prefrontal cortex of AD patients the behavioral and psychotic symptoms. Apathy has also

have been shown to lead to cognitive deﬁcits in contrast to been associated with reduced dopaminergic activity

the neuropsychiatric symptoms observed in FTD [76]. [88]. Interestingly, a randomized controlled trial with

Collectively, these studies indicate that 5-HT1A and 5- the 5-HT2C antagonist agomelatine has shown promis-

HT2A receptors are involved in the pathophysiology of ing results with improvement in apathy and an indirect

both AD and FTD. increase in prefrontal dopaminergic tone in FTD

patients [89 ]. Clinical trials of agomelatine in AD

mGluR5 and the NMDA receptors are co-localized in and PD patients also indicate a reduction in apathy

cortical brain regions and act in a cooperative fashion and depression in AD patients [90] and a signiﬁcant

[77,78]. Speciﬁcally, mGluR5 is involved in the induction decrease in depression and motor symptoms of PD [91],

of NMDA receptor-dependent forms of synaptic plastic- indicating the involvement and beneﬁcial effects of

ity and excitotoxicity [78]. Leuzy et al. [79 ] recently targeting the 5-HT2C receptor in three neurodegenera-

showed a decrease in mGluR5 availability in paralimbic tive disorders.

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102 Neurosciences

Vascular dementia serotonergic system as a therapeutic target in both VaD

VaD is the second most common cause of dementia and is and AD.

associated with multiple cerebrovascular pathologies

[7 ,8 ]. MRI studies reveal cortical and subcortical micro- Clinical trials of FDA approved AD drugs such as done-

infarcts and atrophy of the frontal and temporal lobes, pezil, an acetylcholinesterase inhibitor, galantamine, a

hippocampus, and striatum of VAD patients [7 ,92] nicotinic acetylcholine receptor agonist, and memantine,

(Figure 1c). The M1 muscarinic acetylcholine receptor a NMDAR antagonist, have been conducted with VaD

(M1R) has been shown to be involved in cognitive patients with some positive cognitive outcomes [107,108];

function [93]. In this regard, hippocampal damage caused however, GPCRs have not been extensively studied in

by cerebrovascular occlusion leads to a reduction in the VaD patients but provide additional neurochemical tar-

number of M1Rs and reduced [ H]quinuclidinyl benzi- gets for therapeutic intervention in VaD.

late binding to all muscarinic acetylcholine receptors in

the hippocampus of a chronic cerebral hypoperfusion Parkinson’s disease

(CCH) rat model of VaD [94,95]. In addition, D1Rs have GPCRs and cognitive deﬁcits in PD

been shown to elicit long-term potentiation and enhance PD is a neurodegenerative disease with clinical features

memory storage in the hippocampus [96,97]. A reduction that include motor and non-motor symptoms [13,109].

in D1Rs has been reported in CCH rats. Agonist-induced Approximately 25% of individuals with PD develop mild

activation of the D1R in the dentate gyrus (DG) attenu- cognitive impairment (MCI) [110], including attention,

ates the cognitive impairments in CCH rats [98 ]. These executive function, episodic memory, visuoperceptual/

studies indicate that both M1Rs and D1Rs are involved in visuospatial function, and language deﬁcits [111 ]. A 20-

cognitive function in CCH VaD models. year follow-up study indicates that approximately 80% of

PD patients develop dementia (PDD) [112]. Patholog-

GABAB receptors in the DG regulate synaptic plasticity, ically, MRI studies of PD patients with MCI have

learning, and memory [99]. Lower levels of GABABR1 reduced volume of the nucleus accumbens (NAc)

and GABABR2 have been reported in the hippocampus of [113,114 ], thalamus [113], and amydala [114 ] relative

CCH rats. Administration of the GABABR agonist baclo- to cognitively normal individuals with PD (Figure 2a);

fen to CCH rats leads to an increase in GABABR expres- however, changes in the volume of the thalamus and the

sion and an improvement in spatial learning and memory amydala appear to be PD cohort-dependent.

[100]. In contrast, increased GABABR activity in the

hippocampus of CCH rats has also been observed, and The dopamine D1 and D2 receptors (D1R and D2R) are

treatment with the GABABR antagonist saclofen has been highly expressed in multiple brain regions, including the

shown to improve spatial learning and memory [101 ]. striatum, NAc, and substantia nigra [115]. Levels of both

receptors are elevated in PD patients and are associated

Interestingly, combinatorial treatment with acamprosate, with the development of dopamine denervation super-

which reduces glutamatergic neurotransmission, and the sensitivity [116]. Infusion of the D1R partial agonist SKF

GABABR agonist baclofen has been shown to regulate the 38393, but not the D2R agonist quinpirole, into the NAc

balance between excitatory and inhibitory neuronal sig- of wildtype rats enhanced the accuracy of visuospatial

naling, protecting against Ab-induced neurotoxicty and discrimination [117], whereas treatment with a D1R

alleviating cognitive deﬁcits in an AD mouse model antagonist SCH 23390 decreased accuracy [117], indicat-

[102 ]. The drug PXT864, a combination of baclofen ing that the D1R is involved in visuospatial function.

and acamprosate, is currently in the phase II clinial trials Treatment with the D2R antagonist sulpiride or D2R

for the treatment of AD [103]. These reports suggest the knockdown in the NAc reduced attention performance or

GABABR plays an important role in cognitive function induced attention impairment [118 ], respectively, which

and that further study of the GABABRs will be necessary suggests that the D2R is involved in the regulation of

to delineate the role of these GPCRs in VaD. attention. Taken together, these studies provide evi-

dence to support a role for the D1R and the D2R involved

5-HTRs are abundant in the frontal and temporal cortices in visuospatial and attentional dysfunction in PD-MCI,

[75,104,105] and have been shown to play an important respectively.

role in cognition and memory formation. Increased [( H)-

WAY 100635] and [( H)-ketanserin] radioligand binding GPCRs and motor impairments in PD

has been reported in post-mortem brain samples from Dopamine deﬁciency within the basal ganglia leads to

patients to 5-HT1A and 5-HT2A receptors, respectively, parkinsonian motor symptoms, including bradykinesia,

possibly due to decreased 5-HT availability. Additionally, muscular rigidity, rest tremor, and postural and gait

5-HT1A receptors binding positively correlates with pre- impairment [13]. MRI studies have shown that degener-

served cognition based on the mini-mental state exam ation of the putamen nucleus, which is part of the striatum

[106]. Reduced 5-HT1A receptors in AD brains leads to and basal ganglia, correlate with the motor deﬁcits

cognitive impairments [76], further highlighting the observed in PD [119]. Currently, dopamine replacement

Current Opinion in Pharmacology 2017, 32:96–110 www.sciencedirect.com

Role of GPCRs in neurodegenerative diseases Huang, Todd and Thathiah 103

Figure 2

(a) Parkinson’s Disease

NA A

(b) Huntington’s Disease

C P

Current Opinion in Pharmacology

Schematic representation of the association between brain atrophy and clinical symptoms observed in Parkinson’s disease and Huntington’s

disease, both of which display motor impairments. Blue indicates brain regions that undergo atrophy and are associated with cognitive deficits.

Orange indicates brain regions that undergo atrophy and are associated with motor impairments. Abbreviations for the indicated brain regions

include: amygdala (A), caudate (C), nucleus accumbens (NA), putamen (P), thalamus (T).

therapy with levodopa (L-dopa), a chemical precursor of have been developed to reduce the adverse effects asso-

dopamine, is the most effective drug for the symptomatic ciated with L-dopa therapy [121]. The agonists display

treatment of PD [120]. However, higher doses of L-dopa better pharmacokinetic and pharmacodynamic properties

are required to compensate a decline in clinical efﬁcacy than L-dopa with reduced incidence or delayed onset of

after long-term L-dopa therapy, which results in adverse dyskinesia [121]. Currently, the D1R agonist rotigotine

effects, such as motor ﬂuctuations and motor complica- and the D2R agonists bromocriptine and lisuride have

tions such as dyskinesia [120]. Several D1R and D2R been used as a monotherapy or an adjunctive therapy to

agonists, including rotigotine, bromocriptine and lisuride, L-dopa for the treatment of PD motor symptoms

www.sciencedirect.com Current Opinion in Pharmacology 2017, 32:96–110

104 Neurosciences

[122,123]. However, similar to L-dopa, dopamine agonist Chronic glutamate-mediated excitotoxicity has been sug-

therapy also leads to a decline in efﬁcacy with long-term gested to contribute to disease progression [132].

treatment, limiting the use of dopaminergic therapy. A mGluRs, including mGluR2 and mGluR5, are widely

promising non-dopaminergic alternative is the A2AR expressed in the brain in the neocortical layers, hippo-

antagonist istradefylline, which was recently approved campus, striatum, thalamus/hypothalamus, and cerebel-

in Japan as a combination therapy with L-DOPA to treat lum. Activation of presynaptic mGluR2 [133] and block-

motor dysfunction in PD without increasing the risk of ade of postsynaptic mGluR5 [134] inhibit glutamate

dyskinesia [124 ,125]. These studies suggest that a com- release and prevent excitotoxicity. Treatment of R6/2

bination therapy could be an alternative approach for the HD transgenic mice, which express the N-terminally

treatment of parkinsonian motor symptoms. truncated human HTT with 141–157 CAG repeats,

with either the mGluR2 agonist LY379268 or the

A balance between the dopaminergic and cholinergic mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyri-

system is important in PD [126]. Reduced striatal dine (MPEP) leads to a reduction in hyperactivity

dopamine in PD leads to overactivity of cholinergic [135]. MPEP treatment also reduces the decline in

interneurons and excess acetylcholine release in the motor coordination [135]. Consistent with these ﬁndings,

Q111/Q111

striatum [126]. Anticholinergics such as trihexyphenidyl genetic deletion of mGluR5 in Hdh knock-in

and biperiden, which are selective for the M1R, are mice, which express a 109 CAG repeat insertion, leads to

effective in reducing tremors in PD patients [13]. an improvement in motor coordination and a reduction

Anticholinergics show little effect on bradykinesia in HTT aggregation [135]. These studies suggests that

and rigidity, suggesting a speciﬁc role for M1Rs in mGluRs regulate motor function and HTT protein

PD-associated tremor. Genetic deletion of the musca- aggregation in HD.

rinic acetylcholine receptor 4 (M4R) in mice reduces

antipsychotic-induced catalepsy [127], a PD motor Accumulation of the mutant HTT protein is considered

symptom, supporting a role for the muscarinic acetyl- to initiate the cytotoxicity which leads to HD. A recent

choline receptors in PD motor symptoms. Conversely, study reported that knockdown of the orphan GPCR

dopamine agonists, used to treat motor symptoms, may GPR52, which is highly expressed in the striatum, re-

Q140/Q140

worsen cognition in PD patients, thereby complicating duces HTT protein levels in the striatum of Hdh

therapeutic options in patients suffering with PD with mice by promoting HTT clearance and suppresses HD

dementia (PDD) [128]. phenotypes in both patient-induced pluripotent stem

cell (iPSC)-derived neurons and in a Drosophila HD

Two orphan GPCRs, GPR37 and GPR55, have also been model [136 ], suggesting that striatal degradation of

implicated in motor coordination [129,130]. Interestingly, mutant HTT requires the GPR52-mediated upregulation

in a drug-induced parkinsonian tremor model, genetic of cyclic adenosine monophosphate (cAMP) levels.

deletion of Gpr37 leads to an attenuation of tremulous jaw

movements (TJMs) in response to the nonselective mus- In both humans and HD animal models, D1R and D2R

carinic acetylcholine receptor agonist pilocarpine [131]. expression is reduced in early and late stage HD [137]. In

Treatment with the A2AR antagonist SCH-58261 also early stage HD, patients experience hyperkinesia, poten-

attenuates pilocarpine-induced TJMs [131], an effect tially due to hyperactivity of the dopamine pathway [138].

which is not observed in GPR37-deﬁcient mice. Collec- In contrast to GPR52, activation of the D2R, which

tively, these studies suggest that strategies aimed at the interacts with Gai and negatively regulates cAMP levels,

two orphan GPCRs may represent an alternative thera- has been shown to lead to an increase in HTT aggregation

peutic avenue for intervention in PD. [138] whereas inhibition of the D2R with the antagonist

haloperidol has been shown to reduce HTT aggregation

and protect against striatal cell death, which may be

Huntington’s disease beneﬁcial in the early stages of HD [139].

HD is a progressive neurodegenerative disorder that

presents clinically with involuntary movements, impaired D1R antagonists have also been studied in HD. The D1R

coordination, depression, and slowed cognitive function. antagonist SCH23390 has been shown to prevent dopa-

HD is caused by a CAG trinucleotide repeat expansion in mine- and glutamate-induced cell death in YAC128 mice

the ﬁrst exon of the Huntingtin (Htt) gene. The CAG [140], which express multiple copies of the full-length

repeats vary from 6 to 35 nucleotides in unaffected human mutant HTT protein with 128 glutamine repeats,

individuals. A longer series of CAG repeats (>36) are mainly composed of CAG repeats and nine interspersed

present in HD patients and inversely correlate with the CAA repeats. These studies suggest that GPR52-, and

age of onset [15]. Structural MRI studies indicate exten- D1R-/D2R-speciﬁc signaling regulate HTT degradation

sive degeneration of the striatum and, to a lesser extent, and aggregation, respectively, and may serve as potential

the globus pallidus, thalamus, and hippocampus in HD therapeutic targets for HD drug discovery. These studies

patients [14] (Figure 2b). also suggest that striatal-enriched modulators of HTT

Current Opinion in Pharmacology 2017, 32:96–110 www.sciencedirect.com

Role of GPCRs in neurodegenerative diseases Huang, Todd and Thathiah 105

levels may contribute to the selective vulnerability of These GPCRs represent potential opportunities for the

striatal neurons. Further studies will be required to deter- development of disease-modifying therapies. Given the

mine whether the D1Rs, D2Rs, and GPR52 are involved symptom heterogeneity of and the variety of GPCRs

in the motor impairments observed in HD patients. implicated in disease progression of different neurode-

generative disease, a combinatorial therapeutic approach,

The cannabinoid type 1 receptor (CB1R) has been shown targeting multiple GPCRs, may prove to be beneﬁcial to

to mitigate HTT aggregation in the R6/2 HD mouse slow and perhaps halt disease progression. In this regard,

model. The CB1R is normally highly expressed at syn- inhibition of both the A2AR and CRHR1 may improve

apses in the neocortex, hippocampus, and basal ganglia cognitive function and reduce depression in AD patients.

[141]; however, CB1R levels are reduced in R6/2 mice A combination of of OXTR and DR agonists in FTD

[142]. Moreover, chronic treatment of R6/2 mice with the patients may alleviate the neuropsychiatric and motor

CB1R agonist D -tetrahydrocannabiol (THC) in R6/2 symptoms. Furthermore, mechanistic studies to under-

alleviated motor symptoms relative to vehicle-treated stand the interaction between different neurochemical

animals [142]. In PC12 cells expressing a mutation in pathways are critical to reduce potential side-effects

the HTT [143], activation of the CB1R, which couples to associated with monotherapies. As such, the combination

Gai, with the CB1R agonists HU210 or WIN55212-2 has therapy of L-DOPA and the A2AR antagonist istradefyl-

been shown to alleviate the cell death associated with line, which target two neurochemical pathways, have

HTT aggregation. Taken together, these studies high- reduced side-effects relative to L-DOPA monotherapy

light CB1R agonists as potential therapeutics for HD and in PD patients. Abnormal accumulation of the proteins

suggest a complex role for cAMP in HTT aggregation and mentioned in this review also leads to various pathological

degradation. changes in the brain, including mitochondrial dysfunc-

tion, oxidative stress, and neuroinﬂammation. Therefore,

The A2AR has also been proposed to be a therapeutic an alternate avenue for therapeutic intervention is to

target for HD. A2ARs are localized throughout the brain target the GPCRs involved in neuroprotection. In this

but are primarily found in medium spiny neurons in the regard, neuropeptides acting on GPCRs, such as vasoac-

striatum [144]. Presynaptically, the A2AR antagonist tive intestinal peptide pituitary adenylate cyclase-activat-

SCH58261 in combination with the D1R antagonist ing polypeptide have been shown to inhibit mitochon-

SCH23390 has been shown to play a potentially neuro- drial apoptotic pathways, and protect neurons against

protective role in HD by decreasing glutamate release or oxidative stress-induced apoptosis and inﬂammation, pro-

enhancing glutamate uptake [144,145]. In contrast, viding an alternate avenue for therapeutic intervention in

SCH58261 and SCH23390 have been shown to promote neurodegenerative diseases [147,148]. Collectively, the

neurotoxicity when acting on postsynaptic A2ARs [145]. evidence indicates several viable avenues for therapeutic

In addition, the A2AR agonist CGS21680 has been shown intervention in neurodegenerative diseases.

to be neuroprotective by reducing NMDA currents in

stiatal medium spiny neurons [145] and to delay the onset Conﬂict of interest statement

of motor deterioration in R6/2 mice [146]. Thus, A2AR Nothing declared.

agonists and antagonists appear to provide some protec-

tion in animal models of HD. Although the A2AR is clearly References and recommended reading

involved in the pathophysiology of HD, further investi- Papers of particular interest, published within the period of review,

have been highlighted as:

gation into whether activation or inhibition of the A2AR is

warranted to establish the most advantageous avenue for of special interest

of outstanding interest

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