The role of GPCRs in neurodegenerative diseases:avenues for therapeutic interventionYunhong Huang1, Nicholas Todd2 and Amantha Thathiah1,2,3,4

Available online at www.sciencedirect.com

ScienceDirect

Neurodegenerative diseases represent a large group of

neurological disorders with heterogeneous clinical and

pathological profiles. The majority of current therapeutic

strategies provide temporary symptomatic relief but do not

target the underlying disease pathobiology and thus do not

affect disease progression. G protein-coupled receptors

(GPCRs) are among the most successful targets for therapeutic

development of central nervous system (CNS) disorders. Many

current clinical therapeutic agents act by targeting this class of

receptors and downstream signaling pathways. Here, we

review evidence that perturbation of GPCR function

contributes to the pathophysiology of various

neurodegenerative diseases, including Alzheimer’s disease,

Frontotemporal dementia, Vascular dementia, Parkinson’s

disease, and Huntington’s disease.

Addresses1Department of Neurobiology, University of Pittsburgh School of

Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA2University of Pittsburgh Brain Institute, University of Pittsburgh School

of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA3Pittsburgh Institute for Neurodegenerative Diseases, University of

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

PA 15213, USA4KU Leuven Center for Human Genetics, Leuven 3000, Belgium

Corresponding author: Thathiah, Amantha (amantha@pitt.edu)

Current Opinion in Pharmacology 2017, 32:96–110

This review comes from a themed issue on Neurosciences

Edited by David Chatenet and Terence E. Hebert

For a complete overview see the Issue and the Editorial

Available online 10th March 2017

http://dx.doi.org/10.1016/j.coph.2017.02.001

1471-4892/ã 2017 Elsevier Ltd. All rights reserved.

IntroductionNeurodegenerative diseases are a major cause of disabil-

ity and premature death among the elderly people world-

wide [1]. Alzheimer’s disease (AD), Vascular dementia

(VaD), Frontotemporal dementia (FTD), Parkinson’s

disease (PD), and Huntington’s disease (HD) are the

among the most prevalent neurodegenerative diseases

[2]. AD is the most common neurodegenerative disease

and the predominant cause of dementia in the population

over 65 years of age. AD is characterized by impaired

Current Opinion in Pharmacology 2017, 32:96–110

cognitive function, memory loss, and negative personality

changes [3–5]. The pathological features of AD include

the accumulation of amyloid b (Ab) in amyloid plaques

and hyperphosphorylated aggregates of the microtubule-

associated protein tau in neurofibrillary tangles, which are

first detected in the frontal and temporal lobes and then

slowly progress to the other areas of the neocortex [5].

VaD is the second most common cause of dementia with a

variable age of onset. VaD patients display a disturbance in

frontal executive function [6] and multiple cerebrovascular

pathologies, including vessel occlusion, arteriosclerosis,

hypertensive, aneurysms, and various forms of arteritis

[7�,8�]. Frontotemporal dementia (FTD) is a major cause

of dementia in persons under the age of 65 [9] and

is characterized by neuropsychiatric symptoms and

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

pathological features of FTD include the abnormal depo-

sition of three major proteins—tau, transactive response

DNA-binding protein 43 (TDP-43), and fused in sarcoma

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

pus, frontal cortex, and striatum [11].

Parkinson’s disease (PD) is second most common neuro-

degenerative disease, with an average onset of 50–60

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

non-motor symptoms. The prominent motor symptoms

in PD patients include bradykinesia, rigidity, tremor, and

gait disorders [13]. Non-motor clinical features include

cognitive impairment and neuropsychiatric symptoms

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

tion of Lewy bodies and abnormal aggregates of the

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

substantia nigra and temporal cortex, and the loss of

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

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

repeat expansion in the Huntingtin (Htt) gene [14].

The CAG repeats vary from 6 to 35 nucleotides in

unaffected individuals. A longer series of CAG repeats

(>36) are present in HD patients and inversely correlate

with the age of onset [15]. The deposition of HTT is

most frequent in the cerebral cortex, and much less in

other brain regions such as striatum, hippocampus, and

cerebellum [16]. Collectively, AD, VaD, FTD, PD,

and HD are neurodegenerative diseases with clinical

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

features that include cognitive deficits, motor impair-

ments, and neuropsychiatric symptoms.

G protein-coupled receptors (GPCRs) have been impli-

cated in the pathogenesis of several neurodegenerative

diseases [17,18], including AD, VaD, FTD, PD, and HD.

GPCRs are the largest family of membrane proteins [19].

Over 370 non-sensory GPCRs have been identified of

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

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

immune regulation, cognition, and synaptic transmission

[20]. GPCR ligands include a variety of molecules such as

photons, ions, biogenic amines, peptide, hormones,

growth factors, and lipids [21]. Consequently, GPCRs

represent the most common target for therapeutic drugs.

Here, we mainly focus on the GPCRs that have been

reported in the past 5 years and several well-documented

GPCRs that have been reported to be involved in the

pathophysiology of the neurodegenerative diseases

mentioned above. We review the correlation between

changes in GPCR expression and/or activity with the

neuropathological hallmarks and clinical symptoms

of these neurodegenerative diseases and discuss the

currently available therapeutic strategies targeting the

GPCRs discussed in the text.

Alzheimer’s diseaseGPCRs and cognitive deficits in AD

AD leads to significant degeneration of various brain

regions and the alteration of multiple neurochemical

pathways. Magnetic resonance imaging (MRI) studies

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

campus and entorhinal cortex, which are affected early in

disease progression [5,22], and cortical thickness of the

medial temporal, inferior temporal, temporal pole, angu-

lar gyrus, superior parietal, superior frontal, and inferior

frontal cortex correlate with the cognitive deficits

observed in AD patients [3] (Figure 1a). Furthermore,

changes in multiple neurochemical pathways, including

the acetylcholine, serotonin, adenosine pathways have

been shown to be involved in the cognitive impairments

observed in AD.

Currently, there is no effective treatment for AD. Levels

of acetylcholine are reduced in the brains of AD patients

[23]. As such, acetylcholinesterase inhibitors have been

shown to temporarily ameliorate disease symptoms [24]

by decreasing acetylcholine breakdown, which results in

an increase in cholinergic neurotransmission and a mild

improvement in cognitive function. Excitotoxicity due

to overstimulation of glutamatergic neurotransmission

[25] is also associated with the pathophysiology of AD

[26]. Memantine is an N-methyl-D-aspartate (NMDA)

receptor antagonist that inhibits NMDA receptor-medi-

ated calcium influx into neurons [27] and protects exces-

sive glutamate-induced neuronal death and excitotoxicity

[26], providing temporary improvement in cognitive

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function [28]. Acetylcholinesterase inhibitors and mem-

antine are the only available symptomatic treatments that

slow the decline in cognitive function in individuals with

AD [24]. In this section, we highlight some of the GPCRs

that have been rigorously evaluated in the modulation

of cognitive function in AD mouse models in recent

literature. Additional GPCRs that have been implicated

in the pathophysiology of AD have been included in

Table 1.

Glutamate receptors mediate most of the excitatory neu-

rotransmission in the mammalian brain [29]. The meta-

botropic glutamate receptor (mGluR) family mediate

glutamate neurotransmission. MGluR5 has been shown

to be involved in cognitive function and Ab generation.

Genetic deletion of mGluR5 has been shown to alleviate

cognitive impairment and Ab production in an APPswe/PSEN1DE9 AD mouse model, which overexpresses

human APP harboring the Swedish mutation and human

presenilin 1 lacking exon 9 [30]. Interestingly, pharmaco-

logical inhibition of mGluR5 with 3-[(2-methyl-1,3-thia-

zol-4-yl)ethynyl]-pyridine (MTEP), an antagonist, has

also been shown to alleviate the cognitive deficits in

the same AD mouse model [31]. Similarly, treatment

with the mGluR5 negative allosteric modulator 2-

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

1H-imidazol-4-yl)ethynyl) pyridine (CTEP) alleviates

the cognitive deficits and reduces the amyloid plaque

burden in two AD mouse models [32]. These studies

suggest that allosteric modulators of mGluR5 may be an

effective therapeutic strategy for some AD cases.

Extensive serotonergic denervation of the neocortex and

hippocampus has been observed in AD patients. Reduc-

tion in 5-hydroxytryptamine (5-HT, serotonin) and 5-

HT1A, 5-HT2A, 5-HT4, and 5-HT6 receptor levels have

been reported in the hippocampus and/or prefrontal

cortex of AD patients. In rodent models, activation of

5-HT2A and 5-HT4 receptors leads to an improvement in

hippocampal-dependent learning and memory [33,34] via

G protein- or b-arrestin-dependent activation of extracel-

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

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

receptors has been shown to ameliorate the memory

deficits in a rat AD model [37,38], possibly through an

inhibition of Gi signaling and activation of protein kinase

A (PKA), which leads to the activation of the NMDA

receptor [39,40]. Interestingly, both 5-HT6 receptor ago-

nists and antagonists enhance learning and memory [41]

through potentially different mechanisms of action. Acti-

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

Gs protein-dependent brain-derived neurotrophic factor

(BDNF) mRNA expression and Fyn kinase-dependent

activation of ERK1/2 in wild-type rats [42]. Both BDNF

and ERK1/2 have been shown to be associated with

cognitive function [43,44]. In contrast, 5-HT6 receptor

antagonists have been shown to stimulate glutamate and

Current Opinion in Pharmacology 2017, 32:96–110

98 Neurosciences

Figure 1

Alzheimer’s Disease(a)

(b)

(c)

Frontotemporal Dementia

PRIPL

PC

EC HP

TP H

P

ITG

MTG

SACC

MPC

OFC

TP

A

STG

MTG

Vascular Dementia

DPC

HP ITGMTG

DPC

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

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

acetylcholine release in rat brains, which has been shown

to improve scopolamine- and MK-801-induced deficits in

associative learning [42]. These studies support the

potential benefit of selective modulation of the 5-HT

receptor subtypes for AD therapy.

Expression of the adenosine A1 and A2A receptors (A1R

and A2AR) has been reported to be elevated in the frontal

cortex of the human AD brain [45]. Caffeine, a nonselec-

tive AR inhibitor, has been shown to enhance memory

consolidation in humans [46] and reduce Ab levels and

improve cognitive function in an AD mouse model [47].

Similarly, caffeine and the A2AR antagonist SCH58261

has been shown to be protective against Ab-inducedcognitive impairment [48]. Interestingly, conditional

deletion of astrocytic A2ARs has been shown to enhance

alleviate the memory deficits in AD transgenic mice

through Gs-coupled signaling [49��], whereas activation

of the Gi-coupled A1R and inhibition of PKA has been

shown enhance long-term depression (LTD) [50]. These

studies potentially suggest that activation of Gs-coupled

receptors, such as the A2AR, which activates PKA, may

suppress LTD and promote long-term plasticity (LTP),

whereas Gi-coupled receptors, such as the A1R may be

involved in the induction of LTD.

In addition to GPCRs with identified ligands, the orphan

GPCR GPR3 has been shown to modulate Ab generation

and cognitive function in vivo. Levels of GPR3 are

elevated in the human AD brain [51,52]. Genetic deletion

of Gpr3 has been shown to alleviate the learning and

memory deficits in an AD mouse model and reduce

amyloid pathology in four AD mouse models [53��].The GPR3-mediated effect on amyloid pathology

involves b-arrestin recruitment, independently of Gs-

coupling [51]. A more comprehensive discussion on the

GPCRs involved in the pathogenesis of AD is the subject

of recent reviews [54,55]. Together with the GPCRs such

as 5-HT receptors, adenosine receptors that are involved

in affected neurochemical pathways in AD suggest viable

therapeutic avenues for the treatment of cognitive deficits

in AD.

GPCRs and neuropsychiatric symptoms in AD

The corticotrophin-releasing hormone (CRH) receptor

1 and 2 (CRHR1 and CRHR2) are GPCRs associated

with depression [56,57��]. Interestingly, a greater density

of amyloid plaques has been observed in the hippocam-

pus of AD patients with a previous history of major

depression [58]. Reports also show that genetic deletion

(Figure 1 Legend Continued) brain regions that undergo atrophy and are a

regions that undergo atrophy and are associated with motor impairments. A

anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DPC), entorhi

lobule (IPL), inferior temporal gyrus (ITG), medial prefrontal cortex (MPC), m

posterior cingulate (PC), precuneus (PR), striatum (S), superior temporal gyr

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of Crhr1 in the PSAPP AD mouse model, which over-

express a chimeric mouse/human APP gene with human

APP Swedish mutation and human presenilin 1 lacking

exon 9, leads to a reduction in amyloid pathology [59�].Pharmacological studies in the Tg2576 AD mouse model,

which overexpresses human APP with the Swedish muta-

tion, with the CRHR1 antagonist antalarmin in acutely (7-

days) or in chronically (9-months) stressed mice reduces

Ab production and involves the Gs signaling pathway

[60]; however, pre-treatment with antalarmin failed to

inhibit an increase in Ab levels in acutely (3-hours)

stressed wild-type mice. In vitro cell-free g-secretaseactivity assays with the CRHR1 antagonists astressin,

antalarmin, and NBI-27914 have been shown to modulate

Ab generation in the absence of CRHR1, suggesting that

the compounds tested may have CRHR1-independent

effects on the modulation of g-secretase activity [57��].Treatment of wild-type mice with the CRHR1 antagonist

antalarmin reduces depression-like behaviors, whereas

genetic deficiency of Crhr2 leads to an increase in depres-

sion-like behaviors [61]. Although both receptors have

considerable sequence similarity, the two receptors have

different expression patterns in the brain and affinities for

CRH [62]. Interestingly, CRHR1 is more abundantly

expressed in the pituitary gland, and atrophy of this

region is associated with the neuropsychiatric symptoms

in AD [63]. The in vivo studies suggest that a highly

selective antagonist specific for CRHR1 may be benefi-

cial for the symptoms of depression in AD; however,

careful monitoring of Ab levels would also be necessary

to fully assess the therapeutic potential.

Frontotemporal dementiaFTD is a heterogeneous neurodegenerative disease

caused by degeneration and atrophy of the frontal and

temporal lobes. In general, FTD encompasses a wide

range of neuropathologies associated with mutations in

several genes, including tau, TDP-43, and FUS, which

leads to deterioration in behavior, personality, and motor

functions [10]. MRI and single-photon emission comput-

erized tomography (SPECT) reveal abnormalities and

atrophy in the frontal and temporal lobes of FTD

patients. Further post-mortem examination of FTD

patient brains shows additional degeneration of the stria-

tum [64] (Figure 1b). FTD patients present with a variety

of neuropsychiatric, behavioral, motor, and cognitive

impairments [64,65] including decline in social skills,

depression, compulsive behavior, agitation, bradykinesia,

and/or apathy. Symptom heterogeneity has led to multi-

ple diagnostic clinical categories such as behavioral

ssociated with neuropsychiatric symptoms. Orange indicates brain

bbreviations for the indicated brain regions include: amygdala (A),

nal cortex (EC), hypothalamus (H), hippocampus (HP), inferior parietal

edial temporal gyrus (MTG), orbitofrontal cortex (OFC), pituitary (P),

us (STG), and temporal pole (TP).

Current Opinion in Pharmacology 2017, 32:96–110

100

Neurosciences

Table 1

GPCRs that have been studied in humans and/or animal models

AD FTD VaD PD HD

Cognitive deficits Neuropsychiatric symptoms Neuropsychiatric symptoms Motor impairments Cognitive deficits Motor impairments Cognitive deficits Motor impairments

5-HT1AR [37] 5-HT2AR [149] 5-HT1AR [73,74]a D1R [10,86,87,150]a 5-HT1AR [106] A2AR [131] D1R [117]a A2AR [144,145,151,152]

5-HT2AR [34]a CRHR1 [61]a 5-HT2AR [72–74]a D2R [10,86,87,150]a 5-HT2AR [106] D1R [122] D2R [118�]a D1R [137,140]

5-HT4R [33] CRHR2 [61]a 5-HT2CR [89�]a D1R [98��] D2R [123] D2R [137]

5-HT5AR [38] mGluR5 [79��]a GABABR1 [101�,153] GPR37 [129,131] GPR52 [136�]5-HT6R [41] OXTR [71]a GABABR2 [101�,153] GPR55 [130]a M4R [154]

A1R [48] M1R [94,95] M1R [13] mGluR2 [135]

A2AR [48,49��] M4R [127] mGluR5 [135,155�]BAI1 [156]a mGluR4 [157,158] CB1R [141–143]

CysLT1R [159]

DOR [160]

GABABR [161]a

GIPR [162]a

GPR3 [53��]GPR30 [163]a

GPR48 [164]a

M1R [165]

M3R [166]a

mGluR5 [30]

S1P1 [167]

Abbreviations: 5-HT1AR, 5-hydroxytryptamine receptor 1A; 5-HT2AR, 5-hydroxytryptamine receptor 2A; 5-HT2CR, 5-hydroxytryptamine receptor 2C; 5-HT4R, 5-hydroxytryptamine receptor 4; 5-

HT5AR, 5-hydroxytryptamine receptor 5A; 5-HT6R, 5-hydroxytryptamine receptor 6; A1R, adenosine A1 receptor; A2AR, adenosine A2A receptor; BAI1, brain-specific angiogenesis inhibitor 1; CB1R,

cannabinoid type 1 receptor; CRHR1, corticotrophin-releasing hormone receptor 1; CRHR2, corticotrophin-releasing hormone receptor 2; CysLT1R, cysteinyl leukotriene receptor 1; D1R, dopamine

D1 receptor; D2R, dopamine D2 receptor; DOR, delta-opioid receptor; GABABR, g-Aminobutyric acid B receptor; GIPR, glucose-dependent insulinotropic polypeptide receptor; GPR3, G protein-

coupled receptor 3; GPR30, G protein-coupled receptor 30; GPR37, G protein-coupled receptor 37; GPR48, G protein-coupled receptor 48; GPR52, G protein-coupled receptor 52; GPR55, G

protein-coupled receptor 55; M1R, muscarinic acetylcholine receptor M1; M3R, muscarinic acetylcholine receptor M3;M4R, muscarinic acetylcholine receptor M4; mGluR2, metabotropic glutamate

receptor 2; mGluR4, metabotropic glutamate receptor 4; mGluR5, metabotropic glutamate receptor 5; OXTR, oxytocin receptor; S1P1, sphingosine 1-phosphate receptor.a Studies which were not conducted in animal disease models.

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

variant FTD (bvFTD), primary progressive aphasia

(PPA), semantic dementia (SD), and FTD with parkin-

sonism-17 (FTDP-17) [10]. FTD variants affect both

distinct and overlapping brain regions and multiple neu-

rochemical pathways, which poses a significant challenge

for studying and treating the disease. Here, we discuss the

GPCRs that are the most prominent candidates for ther-

apeutic treatment of the neuropsychiatric and motor

impairments in FTD. A more comprehensive list of

the GPCRs involved in FTD can be found in Table 1.

GPCRs and neuropsychiatric symptoms in FTD

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-

peptide oxytocin is an important mediator of social behav-

ior and neuropsychiatric behaviors in patients with FTD

[66]. In mammals, oxytocin is primarily produced within

the hypothalamic brain regions and is shuttled to the

pituitary for systemic release or projected to various brain

regions for paracrine signaling of the oxytocin receptor

(OXTR) in brain regions such as the amygdala and

anterior cingulate cortex, which have been implicated

in the pathophysiology of FTD [67].

Oxytocin administration has been shown to potentially

improve social interactions [67] and facilitate the devel-

opment of GABAergic synapses, which inhibit signals

that lead to fear and anxiety [68–70]. Interestingly, intra-

nasal administration of oxytocin to FTD patients leads to

improved social interactions, namely patient–caregiver

interactions [71].

Levels of the 5-HT1A and 5-HT2A receptors are reduced

in the anterior cingulate cortex [72] and orbitofrontal and

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

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

Clinically, selective serotonin reuptake inhibitors (SSRIs)

such as fluoxetine, fluvoxamine, and sertraline, which

increase 5-HT levels by blocking 5-HT reuptake, have

been used to provide symptomatic relief for depression

and repetitive or compulsive behaviors observed in

patients with multiple variants of FTD [75]. Interest-

ingly, lower levels of the 5-HT1A and 5-HT2A receptors in

the hippocampus and prefrontal cortex of AD patients

have been shown to lead to cognitive deficits in contrast to

the neuropsychiatric symptoms observed in FTD [76].

Collectively, these studies indicate that 5-HT1A and 5-

HT2A receptors are involved in the pathophysiology of

both AD and FTD.

mGluR5 and the NMDA receptors are co-localized in

cortical brain regions and act in a cooperative fashion

[77,78]. Specifically, mGluR5 is involved in the induction

of NMDA receptor-dependent forms of synaptic plastic-

ity and excitotoxicity [78]. Leuzy et al. [79��] recently

showed a decrease in mGluR5 availability in paralimbic

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cortex and isocortical brain regions of bvFTD patients,

which may precede the neurodegeneration observed in

select frontotemporal brain regions. Electrophysiology

and behavioral studies suggest that mGluR5 activation

enhances NMDA receptor function, whereas mGluR5

inhibition exacerbates the effects of NMDA receptor

blockade [80,81]. These studies suggest that mGluR5

may be in involved in reduced NMDA receptor neuro-

transmission. Interestingly, mGluR5 has also been shown

to play a role in Ab generation, memory, locomotor

function, and anxiety in an AD mouse model, indicating

the multiple functions of the receptor [30].

GPCRs and motor impairments in FTD

The dopamine D1 and D2 receptors (D1R and D2R)

have been reported to play an important role in FTD.

Both the D1R and D2R are most abundantly expressed in

the striatum [82]. Because of disease heterogeneity, both

DR antagonists (antipsychotics) and agonists, which pre-

dominantly target the D2R, have been used to treat FTD.

Clinically, DR antagonists are used to treat behavioral

symptoms such as agitation and disinhibition, and DR

agonists are used to treat motor symptoms such as

rigidity and bradykinesia in bvFTD and FTDP-17,

respectively [10]. Typical antipsychotics such as halo-

peridol and fluphenazine are not commonly used to treat

FTD patients due to neuroleptic side-effects associated

with the high D2R affinity [83]. In contrast, antipsycho-

tics such as olanzapine, quetiapine, and risperidone also

have a high affinity for the D2R, but rapidly dissociate,

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

tion has also been reported to be involved in behavioral

deficits in HD (see below); however, decreased D2R

levels has been reported to be the cause of these impair-

ments [85].

FTDP-17 patients who experience rigidity and brady-

kinesia primarily display a decrease in presynaptic dopa-

minergic nerve terminals and postsynaptic D2R binding

in the striatum. Consequently, FTDP-17 patients are

currently treated with DR agonists such as carbidopa

and levodopa, which have been approved for the treat-

ment of PD [10,86,87] despite potential exacerbation of

the behavioral and psychotic symptoms. Apathy has also

been associated with reduced dopaminergic activity

[88]. Interestingly, a randomized controlled trial with

the 5-HT2C antagonist agomelatine has shown promis-

ing results with improvement in apathy and an indirect

increase in prefrontal dopaminergic tone in FTD

patients [89�]. Clinical trials of agomelatine in AD

and PD patients also indicate a reduction in apathy

and depression in AD patients [90] and a significant

decrease in depression and motor symptoms of PD [91],

indicating the involvement and beneficial effects of

targeting the 5-HT2C receptor in three neurodegenera-

tive disorders.

Current Opinion in Pharmacology 2017, 32:96–110

102 Neurosciences

Vascular dementiaVaD is the second most common cause of dementia and is

associated with multiple cerebrovascular pathologies

[7�,8�]. MRI studies reveal cortical and subcortical micro-

infarcts and atrophy of the frontal and temporal lobes,

hippocampus, and striatum of VAD patients [7�,92](Figure 1c). The M1 muscarinic acetylcholine receptor

(M1R) has been shown to be involved in cognitive

function [93]. In this regard, hippocampal damage caused

by cerebrovascular occlusion leads to a reduction in the

number of M1Rs and reduced [3H]quinuclidinyl benzi-

late binding to all muscarinic acetylcholine receptors in

the hippocampus of a chronic cerebral hypoperfusion

(CCH) rat model of VaD [94,95]. In addition, D1Rs have

been shown to elicit long-term potentiation and enhance

memory storage in the hippocampus [96,97]. A reduction

in D1Rs has been reported in CCH rats. Agonist-induced

activation of the D1R in the dentate gyrus (DG) attenu-

ates the cognitive impairments in CCH rats [98��]. These

studies indicate that both M1Rs and D1Rs are involved in

cognitive function in CCH VaD models.

GABAB receptors in the DG regulate synaptic plasticity,

learning, and memory [99]. Lower levels of GABABR1

and GABABR2 have been reported in the hippocampus of

CCH rats. Administration of the GABABR agonist baclo-

fen to CCH rats leads to an increase in GABABR expres-

sion and an improvement in spatial learning and memory

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

hippocampus of CCH rats has also been observed, and

treatment with the GABABR antagonist saclofen has been

shown to improve spatial learning and memory [101�].

Interestingly, combinatorial treatment with acamprosate,

which reduces glutamatergic neurotransmission, and the

GABABR agonist baclofen has been shown to regulate the

balance between excitatory and inhibitory neuronal sig-

naling, protecting against Ab-induced neurotoxicty and

alleviating cognitive deficits in an AD mouse model

[102�]. The drug PXT864, a combination of baclofen

and acamprosate, is currently in the phase II clinial trials

for the treatment of AD [103]. These reports suggest the

GABABR plays an important role in cognitive function

and that further study of the GABABRs will be necessary

to delineate the role of these GPCRs in VaD.

5-HTRs are abundant in the frontal and temporal cortices

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

role in cognition and memory formation. Increased [(3H)-

WAY 100635] and [(3H)-ketanserin] radioligand binding

has been reported in post-mortem brain samples from

patients to 5-HT1A and 5-HT2A receptors, respectively,

possibly due to decreased 5-HT availability. Additionally,

5-HT1A receptors binding positively correlates with pre-

served cognition based on the mini-mental state exam

[106]. Reduced 5-HT1A receptors in AD brains leads to

cognitive impairments [76], further highlighting the

Current Opinion in Pharmacology 2017, 32:96–110

serotonergic system as a therapeutic target in both VaD

and AD.

Clinical trials of FDA approved AD drugs such as done-

pezil, an acetylcholinesterase inhibitor, galantamine, a

nicotinic acetylcholine receptor agonist, and memantine,

a NMDAR antagonist, have been conducted with VaD

patients with some positive cognitive outcomes [107,108];

however, GPCRs have not been extensively studied in

VaD patients but provide additional neurochemical tar-

gets for therapeutic intervention in VaD.

Parkinson’s diseaseGPCRs and cognitive deficits in PD

PD is a neurodegenerative disease with clinical features

that include motor and non-motor symptoms [13,109].

Approximately 25% of individuals with PD develop mild

cognitive impairment (MCI) [110], including attention,

executive function, episodic memory, visuoperceptual/

visuospatial function, and language deficits [111�]. A 20-

year follow-up study indicates that approximately 80% of

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

ically, MRI studies of PD patients with MCI have

reduced volume of the nucleus accumbens (NAc)

[113,114�], thalamus [113], and amydala [114�] relative

to cognitively normal individuals with PD (Figure 2a);

however, changes in the volume of the thalamus and the

amydala appear to be PD cohort-dependent.

The dopamine D1 and D2 receptors (D1R and D2R) are

highly expressed in multiple brain regions, including the

striatum, NAc, and substantia nigra [115]. Levels of both

receptors are elevated in PD patients and are associated

with the development of dopamine denervation super-

sensitivity [116]. Infusion of the D1R partial agonist SKF

38393, but not the D2R agonist quinpirole, into the NAc

of wildtype rats enhanced the accuracy of visuospatial

discrimination [117], whereas treatment with a D1R

antagonist SCH 23390 decreased accuracy [117], indicat-

ing that the D1R is involved in visuospatial function.

Treatment with the D2R antagonist sulpiride or D2R

knockdown in the NAc reduced attention performance or

induced attention impairment [118�], respectively, which

suggests that the D2R is involved in the regulation of

attention. Taken together, these studies provide evi-

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

in visuospatial and attentional dysfunction in PD-MCI,

respectively.

GPCRs and motor impairments in PD

Dopamine deficiency within the basal ganglia leads to

parkinsonian motor symptoms, including bradykinesia,

muscular rigidity, rest tremor, and postural and gait

impairment [13]. MRI studies have shown that degener-

ation of the putamen nucleus, which is part of the striatum

and basal ganglia, correlate with the motor deficits

observed in PD [119]. Currently, dopamine replacement

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

Figure 2

(a)

(b)

Parkinson’s Disease

Huntington’s Disease

T

P

NA

A

CP

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

dopamine, is the most effective drug for the symptomatic

treatment of PD [120]. However, higher doses of L-dopa

are required to compensate a decline in clinical efficacy

after long-term L-dopa therapy, which results in adverse

effects, such as motor fluctuations and motor complica-

tions such as dyskinesia [120]. Several D1R and D2R

agonists, including rotigotine, bromocriptine and lisuride,

www.sciencedirect.com

have been developed to reduce the adverse effects asso-

ciated with L-dopa therapy [121]. The agonists display

better pharmacokinetic and pharmacodynamic properties

than L-dopa with reduced incidence or delayed onset of

dyskinesia [121]. Currently, the D1R agonist rotigotine

and the D2R agonists bromocriptine and lisuride have

been used as a monotherapy or an adjunctive therapy to

L-dopa for the treatment of PD motor symptoms

Current Opinion in Pharmacology 2017, 32:96–110

104 Neurosciences

[122,123]. However, similar to L-dopa, dopamine agonist

therapy also leads to a decline in efficacy with long-term

treatment, limiting the use of dopaminergic therapy. A

promising non-dopaminergic alternative is the A2AR

antagonist istradefylline, which was recently approved

in Japan as a combination therapy with L-DOPA to treat

motor dysfunction in PD without increasing the risk of

dyskinesia [124�,125]. These studies suggest that a com-

bination therapy could be an alternative approach for the

treatment of parkinsonian motor symptoms.

A balance between the dopaminergic and cholinergic

system is important in PD [126]. Reduced striatal

dopamine in PD leads to overactivity of cholinergic

interneurons and excess acetylcholine release in the

striatum [126]. Anticholinergics such as trihexyphenidyl

and biperiden, which are selective for the M1R, are

effective in reducing tremors in PD patients [13].

Anticholinergics show little effect on bradykinesia

and rigidity, suggesting a specific role for M1Rs in

PD-associated tremor. Genetic deletion of the musca-

rinic acetylcholine receptor 4 (M4R) in mice reduces

antipsychotic-induced catalepsy [127], a PD motor

symptom, supporting a role for the muscarinic acetyl-

choline receptors in PD motor symptoms. Conversely,

dopamine agonists, used to treat motor symptoms, may

worsen cognition in PD patients, thereby complicating

therapeutic options in patients suffering with PD with

dementia (PDD) [128].

Two orphan GPCRs, GPR37 and GPR55, have also been

implicated in motor coordination [129,130]. Interestingly,

in a drug-induced parkinsonian tremor model, genetic

deletion of Gpr37 leads to an attenuation of tremulous jaw

movements (TJMs) in response to the nonselective mus-

carinic acetylcholine receptor agonist pilocarpine [131].

Treatment with the A2AR antagonist SCH-58261 also

attenuates pilocarpine-induced TJMs [131], an effect

which is not observed in GPR37-deficient mice. Collec-

tively, these studies suggest that strategies aimed at the

two orphan GPCRs may represent an alternative thera-

peutic avenue for intervention in PD.

Huntington’s diseaseHD is a progressive neurodegenerative disorder that

presents clinically with involuntary movements, impaired

coordination, depression, and slowed cognitive function.

HD is caused by a CAG trinucleotide repeat expansion in

the first exon of the Huntingtin (Htt) gene. The CAG

repeats vary from 6 to 35 nucleotides in unaffected

individuals. A longer series of CAG repeats (>36) are

present in HD patients and inversely correlate with the

age of onset [15]. Structural MRI studies indicate exten-

sive degeneration of the striatum and, to a lesser extent,

the globus pallidus, thalamus, and hippocampus in HD

patients [14] (Figure 2b).

Current Opinion in Pharmacology 2017, 32:96–110

Chronic glutamate-mediated excitotoxicity has been sug-

gested to contribute to disease progression [132].

mGluRs, including mGluR2 and mGluR5, are widely

expressed in the brain in the neocortical layers, hippo-

campus, striatum, thalamus/hypothalamus, and cerebel-

lum. Activation of presynaptic mGluR2 [133] and block-

ade of postsynaptic mGluR5 [134] inhibit glutamate

release and prevent excitotoxicity. Treatment of R6/2

HD transgenic mice, which express the N-terminally

truncated human HTT with 141–157 CAG repeats,

with either the mGluR2 agonist LY379268 or the

mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyri-

dine (MPEP) leads to a reduction in hyperactivity

[135]. MPEP treatment also reduces the decline in

motor coordination [135]. Consistent with these findings,

genetic deletion of mGluR5 in HdhQ111/Q111 knock-in

mice, which express a 109 CAG repeat insertion, leads to

an improvement in motor coordination and a reduction

in HTT aggregation [135]. These studies suggests that

mGluRs regulate motor function and HTT protein

aggregation in HD.

Accumulation of the mutant HTT protein is considered

to initiate the cytotoxicity which leads to HD. A recent

study reported that knockdown of the orphan GPCR

GPR52, which is highly expressed in the striatum, re-

duces HTT protein levels in the striatum of HdhQ140/Q140

mice by promoting HTT clearance and suppresses HD

phenotypes in both patient-induced pluripotent stem

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

model [136�], suggesting that striatal degradation of

mutant HTT requires the GPR52-mediated upregulation

of cyclic adenosine monophosphate (cAMP) levels.

In both humans and HD animal models, D1R and D2R

expression is reduced in early and late stage HD [137]. In

early stage HD, patients experience hyperkinesia, poten-

tially due to hyperactivity of the dopamine pathway [138].

In contrast to GPR52, activation of the D2R, which

interacts with Gai and negatively regulates cAMP levels,

has been shown to lead to an increase in HTT aggregation

[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

beneficial in the early stages of HD [139].

D1R antagonists have also been studied in HD. The D1R

antagonist SCH23390 has been shown to prevent dopa-

mine- and glutamate-induced cell death in YAC128 mice

[140], which express multiple copies of the full-length

human mutant HTT protein with 128 glutamine repeats,

mainly composed of CAG repeats and nine interspersed

CAA repeats. These studies suggest that GPR52-, and

D1R-/D2R-specific signaling regulate HTT degradation

and aggregation, respectively, and may serve as potential

therapeutic targets for HD drug discovery. These studies

also suggest that striatal-enriched modulators of HTT

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

levels may contribute to the selective vulnerability of

striatal neurons. Further studies will be required to deter-

mine whether the D1Rs, D2Rs, and GPR52 are involved

in the motor impairments observed in HD patients.

The cannabinoid type 1 receptor (CB1R) has been shown

to mitigate HTT aggregation in the R6/2 HD mouse

model. The CB1R is normally highly expressed at syn-

apses in the neocortex, hippocampus, and basal ganglia

[141]; however, CB1R levels are reduced in R6/2 mice

[142]. Moreover, chronic treatment of R6/2 mice with the

CB1R agonist D9-tetrahydrocannabiol (THC) in R6/2

alleviated motor symptoms relative to vehicle-treated

animals [142]. In PC12 cells expressing a mutation in

the HTT [143], activation of the CB1R, which couples to

Gai, with the CB1R agonists HU210 or WIN55212-2 has

been shown to alleviate the cell death associated with

HTT aggregation. Taken together, these studies high-

light CB1R agonists as potential therapeutics for HD and

suggest a complex role for cAMP in HTT aggregation and

degradation.

The A2AR has also been proposed to be a therapeutic

target for HD. A2ARs are localized throughout the brain

but are primarily found in medium spiny neurons in the

striatum [144]. Presynaptically, the A2AR antagonist

SCH58261 in combination with the D1R antagonist

SCH23390 has been shown to play a potentially neuro-

protective role in HD by decreasing glutamate release or

enhancing glutamate uptake [144,145]. In contrast,

SCH58261 and SCH23390 have been shown to promote

neurotoxicity when acting on postsynaptic A2ARs [145].

In addition, the A2AR agonist CGS21680 has been shown

to be neuroprotective by reducing NMDA currents in

stiatal medium spiny neurons [145] and to delay the onset

of motor deterioration in R6/2 mice [146]. Thus, A2AR

agonists and antagonists appear to provide some protec-

tion in animal models of HD. Although the A2AR is clearly

involved in the pathophysiology of HD, further investi-

gation into whether activation or inhibition of the A2AR is

warranted to establish the most advantageous avenue for

therapeutic benefit in HD.

ConclusionCurrent therapeutic strategies provide temporary symp-

tomatic relief but do not target the underlying pathobiol-

ogy of the neurodegenerative diseases discussed here and

thus do not affect disease progression. In the current

work, we summarize studies on several GPCRs that are

expressed in degenerative brain regions involved in AD,

VaD, FTD, PD, and HD and present the current evi-

dence, which supports therapeutic intervention strategies

focused on functional modulation of specific GPCRs.

An increasing number of GPCRs are being identified,

which are involved in modulation of the neuropathologi-

cal changes observed in neurodegenerative diseases.

www.sciencedirect.com

These GPCRs represent potential opportunities for the

development of disease-modifying therapies. Given the

symptom heterogeneity of and the variety of GPCRs

implicated in disease progression of different neurode-

generative disease, a combinatorial therapeutic approach,

targeting multiple GPCRs, may prove to be beneficial to

slow and perhaps halt disease progression. In this regard,

inhibition of both the A2AR and CRHR1 may improve

cognitive function and reduce depression in AD patients.

A combination of of OXTR and DR agonists in FTD

patients may alleviate the neuropsychiatric and motor

symptoms. Furthermore, mechanistic studies to under-

stand the interaction between different neurochemical

pathways are critical to reduce potential side-effects

associated with monotherapies. As such, the combination

therapy of L-DOPA and the A2AR antagonist istradefyl-

line, which target two neurochemical pathways, have

reduced side-effects relative to L-DOPA monotherapy

in PD patients. Abnormal accumulation of the proteins

mentioned in this review also leads to various pathological

changes in the brain, including mitochondrial dysfunc-

tion, oxidative stress, and neuroinflammation. Therefore,

an alternate avenue for therapeutic intervention is to

target the GPCRs involved in neuroprotection. In this

regard, neuropeptides acting on GPCRs, such as vasoac-

tive intestinal peptide pituitary adenylate cyclase-activat-

ing polypeptide have been shown to inhibit mitochon-

drial apoptotic pathways, and protect neurons against

oxidative stress-induced apoptosis and inflammation, pro-

viding an alternate avenue for therapeutic intervention in

neurodegenerative diseases [147,148]. Collectively, the

evidence indicates several viable avenues for therapeutic

intervention in neurodegenerative diseases.

Conflict of interest statementNothing declared.

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