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The role of GPCRs in neurodegenerative diseases: avenues for therapeutic intervention Yunhong Huang 1 , Nicholas Todd 2 and Amantha Thathiah 1,2,3,4 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. Addresses 1 Department of Neurobiology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA 2 University of Pittsburgh Brain Institute, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA 3 Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA 4 KU Leuven Center for Human Genetics, Leuven 3000, Belgium Corresponding author: Thathiah, Amantha ([email protected]) Current Opinion in Pharmacology 2017, 32:96–110 This review comes from a themed issue on Neurosciences Edited by David Chatenet and Terence E. He ´ bert 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. Introduction Neurodegenerative 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 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 Available online at www.sciencedirect.com ScienceDirect Current Opinion in Pharmacology 2017, 32:96–110 www.sciencedirect.com

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The role of GPCRs in neurodegenerative diseases: avenues for therapeutic interventionThe role of GPCRs in neurodegenerative diseases: avenues for therapeutic intervention Yunhong Huang1, Nicholas Todd2 and Amantha Thathiah1,2,3,4
Available online at www.sciencedirect.com
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.
Addresses 1Department of Neurobiology, University of Pittsburgh School of
Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA 2University of Pittsburgh Brain Institute, University of Pittsburgh School
of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh, PA 15213, USA 3Pittsburgh Institute for Neurodegenerative Diseases, University of
Pittsburgh School of Medicine, 3501 Fifth Avenue, BST3, Pittsburgh,
PA 15213, USA 4KU Leuven Center for Human Genetics, Leuven 3000, Belgium
Corresponding author: Thathiah, Amantha ([email protected])
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
Introduction Neurodegenerative 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
features that include cognitive deficits, motor impair-
ments, and neuropsychiatric symptoms.
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 disease GPCRs 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.
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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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.
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)-
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
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
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-induced cognitive 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.
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-secretase activity 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 dementia FTD 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
1 0 0
N e u ro s c ie n c e s
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]
GPR48 [164]a
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.
C u rre
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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].
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.
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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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].
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.
102 Neurosciences
Vascular dementia VaD 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 disease GPCRs 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.
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
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
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
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].
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 disease HD 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).
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-
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.
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.
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
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.
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Introduction
Frontotemporal dementia
Vascular dementia
Huntington’s disease