Neurophysiology, Vol. 51, No.

4, July, 2019

REVIEWS

Altered Neurochemistry in Alzheimer’s Disease:

Targeting Neurotransmitter Receptor Mechanisms
and Therapeutic Strategy
S. Kaur,1 G. DasGupta,2 and S. Singh1
Received January 29, 2019

Alzheimer’s disease (AD) is the most common form of dementia characterized by impaired cognitive
functions associated with altered neurotransmitter levels in the brain. In AD with advancement of age,
symptoms that affect memory, learning ability, language perception, and behavior start to progress.
These shifts correlate with accumulations of amyloid beta plaques and neurofibrillary tangles. Such
pathological changes are thought to distort synaptic neurotransmitter levels and interrupt neuron-to-
neuron functioning. The current drugs in AD, like donepezil, rivastigmine, etc., rely to a significant
extent on ameliorated cholinergic neurotransmission and utilization of anticholinesterase inhibitors.
The recent outbreaks in this disease also target neurotransmitters such as dopamine, serotonin, and
their receptor signaling, rather than focusing on cholinergic neurotransmission. This concept emerges
due to findings of altered neurotransmitter levels in the post mortem brains of AD patients. The current
review summarizes some data underlying mechanisms targeting the role of neurotransmitters and their
association with AD, as well as those related to the respective therapeutic aspects. In addition, the
review describes advances in recent drugs targeting neurotransmission preclinically and clinically for
their neuroprotective role in AD.

Keywords: Alzheimer’s disease, neurotransmitters, receptor modulation, endocannabinoids.

INTRODUCTION gonist (memantine), and this is thought to preserve

Alzheimer’s disease (AD) is a peculiar neuro­
degenerative disorder caused by excessive loss
of neurons, mostly in the hippocampus and
cerebral cortex. This pathology is characterized
by cognitive impairment, memory loss, and
behavioral abnormalities. The respective symptoms
start to progress with massive loss of cholinergic
neurons that synthesize acetylcholine (ACh) and
are responsible, to a great extent, for coordinating
memory functions [1]. Currently, the available
therapy for AD includes acetylcholinesterase
inhibitors (rivastigmine, galantamine, and done­
pezil) and a N-methyl D-aspartate receptor anta­
1
Neuroscience Division, Department of Pharmacology, ISF College of
Pharmacy, Moga, Punjab, India.
2
Director ISF College of Pharmacy, Department of Pharmaceutical
sciences, Moga, Punjab, India.
Correspondence should be addressed to S. Singh
(e-mail: shamshersinghbajwa@gmail.com).
cholinergic neurotransmission [2]. Not only
ACh, but other neurotransmitters, like GABA,
glutamate, and serotonin, also contribute to AD
pathophysiology. Recently, these neurotransmitters
are under intense investigation because of their
significant contribution to the learning and memory
phenomena [3]. A number of drugs are at present
subjected to preclinical studies and clinical trials for
assessing their therapeutic effectiveness in AD [4].
The hippocampus and neocortex are the major
areas associated with learning and memory func­
tions, and these have mostly deteriorated in AD.
The recent outbreaks provide evidence regarding
gradual progression of the disease and loss of
neurons in the cortex, hippocampus, amygdala,
thalamus, and some other subcortical regions of
the brain [5]. However, beyond this, a number of
various inward and outward projections towards the
hippocampal regions emphasize the role of certain
neurotransmitters in the coordination of the memory
function [6].

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294 S. Kaur et al.

Acetylcholine (ACh) in AD. monophosphate (cAMP) [10]. The M 1 ACh recep­

Acetylcholine (ACh) is a neurotransmitter of
the cholinergic system, which plays an essential
role in cognitive functions; its level in the brain is
known to be considerably reduced in AD [7]. The
basal forebrain nuclei send significant cholinergic
projections towards the hippocampus, cerebral
cortex, and amygdala [8]. The loss of cholinergic
neurons in the basal forebrain and other regions
is believed to be one of the crucial reasons for
the impairment of memory functions in AD. Post
mortem studies of the brain of AD patients showed
a significant reduction in the ACh level; this is
indicative of the strict relation of such shifts to
disorders of cognition and memory. Acetylcholine
functions through muscarinic ACh (MACh) and
nicotinic ACh (NACh) receptors. Certain evidence
showed that the marked reduction of ACh receptors
is associated with deposition of amyloid β plaques
and neurofibrillary tangles [9]. The expression of
MACh receptors in the brain is well understood, and
recent advancement in their signaling gives reliable
therapeutic outcomes in AD (Table 1).
The activation of M 1 , M 3 , and M 5 ACh recep­
tors increases influx of Ca 2+ and production of
inositol trisphosphate (IP3), whereas M 2 and M 4
activation leads to inhibition of cyclic adenosine
tors in AD affect hippocampal learning, amy­loid­o ­
genesis, and NMDAR-mediated synaptic plasticity,
as evidenced by various animal knockout transgenic
models [11]. The role of M 2 ACh receptors in the
brain is less clear, but this subtype has been reported
to regulate glutamatergic neurotransmission through
hippocampal neurons toward the prefrontal cortex.
Another study emphasized the presence of M 2
receptors on axonal terminals of glutamatergic
afferents, where they modulate the release of
glutamate [12]. The possible role of M 2 receptors
seems to be auto-inhibitory in its nature; their
activation inhibits GABAergic signaling and elicits
the release of glutamate. Further, this action disturbs
the inhibitory/excitatory balance of receptors
and results in the deletion of the M 2 -associated
CHRM-2 gene, which causes a hypercholinergic
state in the mammalian brain [13]. In AD, enhanced
expression of M 2ACh receptors or their long-term
activation produces a neurotoxic effect in the
brain. Activation of M 3 ACh receptors regulates
the non-amyloidogenic pathway (which is known
to be altered in AD), and this further increases
accumulation of amyloid β plaques. The reduced
expression of these receptors in the hippocampus,
amygdala, and entorhinal cortex affects learning

T a b l e 1.
Receptors Location in the brain
Hippocampus,
cerebral cortex, amygdala,
M1
prefrontal cortex,
corpus striatum and thalamus
Cerebellum, thalamus
(nucl. basalis, lower levels),
M2
hippocampus, amygdala,
and caudate/putamen
Cortex, amygdala,
M3 hippocampus, olfactory bulb,
striatum, thalamus, and pons
Hippocampus, dentate gyrus,
M4 caudate/putamen, prefrontal
cortex, and corpus striatum
Pars compacta
of the substantia nigra,
M5
hippocampus, and
of phospholipase Cβ (PLC)
ventral tegmental area
Signalling mechanism Functions
• Synaptic plasticity
• Neuronal excitability,
Subunit α of Gq/11
• Long-term potentiation
mediates activation of
• Neuronal differentiation during the early development
phospholipase Cβ (PLC)
in learning and memory
• Modulation of glutamatergic neurons
Subunit α of Gi and Go
Inhibitory modulatory action on dopaminergic
mediates adenylate
terminals
cyclase activity
• Regulation of food intake
Subunit α of Gq/11
• Regulation of learning and memory
mediates activation of
• Hypoplasia of the anterior pituitary gland
phospholipase Cβ (PLC)
• Promotion of body growth
• Role in cognition
Subunit α of Gi and Go • Implicated in Psychosis, schizophrenia, and
mediates adenylate Parkinson’s disease.
cyclase activity • Inhibition of the D1 function and suppression of
locomotor activity
Subunit α of Gq/11
• Facilitates dopamine release (?).
mediates activation
• Rewarding effect of the abuse drugs.
Neurotransmitter Alteration and Therapeutic Strategy in AD
and leads to declines in memory-associated fear
conditioning [10].
Similarly, M 4ACh receptors are allied to striatal
glutamatergic projections, hippocampus, and cortex,
where they regulate the cognitive functions. The
allosteric modulators of M 4ACh receptors are useful
in the case of cognitive decline and have anti-
psychotic efficacy; these agents became prominent
therapeutic means in AD. Moreover, agonists of
M 4ACh receptor were shown in various preclinical
studies to reduce behavioral disturbances and to
improve cognition and conditioned avoidance
reflexes [11]. Furthermore, M 5 ACh receptors are
predominantly expressed in the cerebral vasculature
where they regulate cerebral blood flow towards
the striatum, cerebral cortex, hippocampus, basal
ganglia, and thalamus. Activation of M 5 ACh
receptors enhances striatal dopamine release and
also mediates ACh-dependent vasodilation of the
cerebral arteries, which was evidenced by genetic
knockout studies [14]. Thus, agents affecting
M 5ACh receptors could appear favorable targeted
drugs for ischemia-associated AD.
Nicotinic receptors are pentameric structural
proteins consisting of five different subunits with
a central hydrophilic pore for the flow of cations,
like Na + , Ca 2+ , and K + . Further, these subunits
have 16 different small loops formed by α (1-7),
α (9,10), β (1-4), γ, δ, and ε components. This
pentameric structure could be homopentameric or
heteropentameric in its nature; it may be α-bunga­
rotoxin-sensitive or insensitive. The nicotinic receptors
are widely expressed not only in neuromuscular
junctions and autonomic ganglia, but also present
in other parts of the brain including neurons and
synapses of hippocampus [15]. Homopentameric α7
NACh and heteropentameric β2α4 nACh receptors
were specifically found to play a vital role in AD.
These subtypes also have a high permeability for
Ca 2+, increase glutamatergic neurotransmission, and
modulate neuronal plasticity via influencing the
axonal growth [16]. Activation of α7 nACh and β2α4
NACh receptors regulates acetylcholine release and
inhibits production of inflammatory cytokines, which
indicates communal contribution of these receptor
subtypes to neuroinflammation and cognitive decline.
Moreover, these receptors are also involved in
neuronal survival via upregulation of a neurotrophic
factor and inhibition of apoptotic factors [17].
Oliviero et al. [18] demonstrated that amyloid
β deposition in synaptosomes induces inhibition
of β 2 α 4 receptors and decreases the functioning
295
of hippocampal areas. There is, however, one
contradictory report showing that amyloid β
provokes activation of β2α4 receptors, as evidenced
by cell line studies. This may occur due to increased
influx of Ca 2+ , which results in mitochondrial
dysfunction and enhanced oxidative stress. One
another recent study reported that amyloid β
deposition promotes neurotoxicity via inhibition
of α 7 NACh receptors followed by ERK activation
[17]. Abnormal protein deposition, like amyloid
β accumulation in the brain, causes dysregulation
in the α 7 NACh receptor functioning in AD.
Additionally, it was reported that direct nicotine
administration for 6 months in human subjects
improves memory and cognition deficits, but side
effects, like addiction and adverse effects on the
cardiovascular system, limit its therapeutic use [16].
Several other molecules targeting nicotinic receptors
are under investigation for the treatment of AD and
are discussed in the management part. In conclusion,
activation of both β 2 α 4 and α 7 NACh receptors
provides noticeable neuroprotective effects in AD
(Fig. 1).
Dopamine in AD.
Dopamine is synthesized in the midbrain and
known to coordinate a number of functions, like motor
functions, cognition, and reward phenomena [19].
A number of studies emphasized that dopaminergic
neurons are lost in AD. Recently, it was revealed [20]
that dopaminergic neurons of the ventral tegmental
area (VTA) are significantly involved in cognition,
formation of memory, and synaptic plasticity.
Degeneration of dopaminergic neurons in the VTA
occurs in early AD, whereas striatum-associated
loss of dopaminergic neurons was found to occur in
later stages. Loss of DA in the striatum contributes
to extrapyramidal symptoms and affects 35-40%
AD patients [21]. Administration of dopaminergic
supplements, like levodopa or a selegiline-like
MAO-B inhibitor, was found to rescue memory
impairment, as well as neuronal loss in the CA1 region
of the hippocampus. The favorable neuroprotective
effect of dopamine in the hippocampus is considered
to be provided by dopaminergic projections targeting
the hippocampal area of the brain. The cerebral cortex
and nucl. accumbens (NAc) are also involved in the
regulation of memory and cognition through the
mesocortico-limbic pathway [20]. The distribution
of dopaminergic neurons in substantia nigra pars
compacta (SNpc) and VTA helps to understand the
role of such units in the coordination of a number of
functions in AD.
296 S. Kaur et al.

F i g. 1. Targeting of α7- and α4β2-NACh receptors as a neuroprotective approach.

Ascending projections from the SNpc reach
the caudate and putamen nuclei where they
form a mesostriatal pathway and participate in
the regulation of voluntary movements; their
loss produces manifestations of extrapyramidal
symptoms (EPSs) in the late AD stages. Projections
originating from the VTA reach the hippocampus,
cerebral cortex, and putamen nuclei where they, via
the mesostriatal pathway, contribute to the control of
memory, reward-related phenomena, and violation
[21]. Both above-mentioned projections are
subjected to degeneration in AD, which determines
the development of the respective associated
symptoms (Fig. 2).

F i g. 2. The meso-striatal pathway and meso-cortical signalling with the limbic system in AD.
Neurotransmitter Alteration and Therapeutic Strategy in AD 297

Both glutamatergic and cholinergic projections Glutamate in AD.

work in parallel, but overexcitation of glutamatergic
pathways spoils the cholinergic projections. The
evidence regarding decreased release of dopamine,
reduction of the number of dopamine receptors,
decreased expression of dopamine transporters, and
decreased activity of tyrosine hydroxylase are well
highlighted by available research reports [20, 21].
Some statements are related only to the decreased
expression of both D1 and D2 receptors in AD,
whereas several recent reports emphasize their
specific role in AD [22].
Similarly, some studies highlight the role of D1
and D2 receptors in cognition via potentiating the
prefrontal cortex (PFC) signaling. Here, D1-like
receptors are more densified in the prefrontal cortex
(PFC); these receptors are involved in the regulation
of working memory, as well as executive functions.
However, there are less D2 receptors in the PFC
but more in the caudate, VTA, and hippocampal
regions; they coordinate hippocampus-related
cognitive functions. The reduced expression of D2
receptors in AD patients has been reported in the
hippocampus, temporal lobe, and VTA. Not only
dopaminergic projections, but also glutamatergic
ones are present in these regions, and they are also
affected and regulate excitotoxicity. Perhaps, this is
an evidence that they make D2 receptors protective
against neuroinflammation and excitotoxicity in AD.
Here, D2 receptors were shown to be noticeably
responsible for episodic memory and executive
functions, which are considered extrastriatal effects
in AD.
Glutamate is an excitatory neurotransmitter
reported to be involved in the coordination of
memory, synaptic plasticity, and neurogenesis.
Glutamate not only plays a neuroprotective role
but also is implemented in the excitotoxicity-
dependent neurotoxic mecha­n isms. The availability
of L-glutamate in the human brain is approximately
6–7 μmol/g, which makes this compound functionally
the most abundant free amino acid. There are three
types of glutamate receptors belonging to the
ionotropic or metabotropic classes. The ionotropic
receptors are further classified as N-methyl-D-
aspartate (NMDA)-, α-amino-3-hydroxy-5-methyl-
4-isoxazolepropionic acid (AMPA)-, and kainate-
type receptors. Functionally, these receptors are
subclassed as ligand-gated ion channels and are
of a metabotropic type; the latter belong to the
GPCR family [23] (Table 2). Both mGluRs1 and
mGluRs5 play crucial roles in the pathology of
AD [24]. The expression of mGluRs1 was found to
decrease in AD, as was revealed through available
animal studies. Only a few findings were targeted
to activation of mGluRs1 by Aβ aggregation [25].
Further, mGluR5 activation leads to Aβ oligomer
formation. CTEP 2-(chloro-4-((2, 5-dimethyl-1-
(4-(trifluoromethoxy) phenyl)-1H-imidazol-4-yl)
ethynyl)pyridine) is one of the negative allosteric
modulators of mGluRs5; it provides an antagonistic
action on the Aβ pathology in AD. Other studies
showed that treatment with antagonists of mGluRs5,
like MTEP (3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]
pyridine), provides the neuroprotective effect in AD.

T a b l e 2.
Group Subtype Location Signalling mechanism
Cerebellar cortex, olfactory bulb, lateral septum, globus pallidus,
mGluR1 Couple to Gq/11, stimulate
entopeduncular nucleus, ventral pallidum, and thalamic nuclei
Group I phospholipase C to release Ca2+,
Cerebral cortex, hippocampus, subiculum, olfactory bulb, striatum,
mGluR5 and enhance glutamate release
nucl. accumbens, and lateral septal nucleus
mGluR 2 Cerebellar cortex and olfactory bulb
Negatively regulate adenylyl
Olfactory tubercle, cerebral cortex, dentate gyrus, lateral septal
Group 2 cyclase via coupling to Gαi
mGluR3 nucleus, striatum, nucl. accumbens, amygdaloid nuclei,
and inhibit glutamate release
substantia nigra pars reticulata, and cerebellar cortex
Cerebellum, olfactory bulb, cerebral cortex, hippocampus,
mGluR4 lateral septum, septofimbrial nucleus, striatum,
thalamic nuclei, and spinal dorsal horn Negatively regulate adenylyl
Group 3 mGluR6 Retina cyclase via coupling to Gαi
mGluR7 expressed widely in the brain and inhibit glutamate release
Olfactory bulb, cerebral cortex, and lateral reticular nucleus
mGluR8
of the medulla oblongata
298
Genetic deletion of mGluR5 in transgenic mice was
reported to reduce Aβ aggregation [26, 27].
The group-II glutamate receptors exhibit some­
what complex results in AD studies. Normally,
activation of mGluRs2 provides neuroprotection
in this disease, but some contradictory reports
showed that overactivation of mGluR2 increases
Aβ production [28, 29]. Activation of group-III
receptors is considered to provide a neuroprotective
effect. Similarly, activation of mGluRs7 prevents
neuronal degeneration in the basal forebrain
nuclei but increases glutamate- and Aβ-dependent
excitotoxicity damage to these nuclei [30].
Ionotropic receptors, like kainate and AMPA ones,
mediate their action through Na + influx, whereas
NMDA receptors provide this via Ca 2+ influx. The
activity of NMDA receptors depends upon Mg 2+ ,
which stabilizes them in the normal state, while
depolarization prevents these receptors from being
activated. The NMDA receptors consist of three
subunits, NR1, NR2 (A, B, C, and D), and NR3
(A and B), which form calcium-permeable ion
channels. The NR1, NR2A, and NR2C subunits
are expressed in the temporal cortical regions and
hippocampus within the embryonic stage; they
spread throughout the brain during the neonatal
development, which is indicative of their role in
neurogenesis. Similarly, the NR2A and NR2B
subunits are known to play an important role in
the induction of memory [31]. The distribution of
F i g. 3. NMDA receptor signalling via NR2A neuroprotective and NR2B neurotoxic events in AD.
S. Kaur et al.
NMDA receptors occurs in presynaptic, synaptic,
and extrasynaptic regions. Synaptic NMDA receptors
are located on the presynaptic areas of axon
terminals; the presynapses are found to be located
200-300 nm away from the postsynaptic regions.
The extrasynaptic NMDA (eNMDA) receptors
are localized on the spine necks, dendritic shafts,
and somata of the neurons, and their activation
requires a high amount of glutamate release. The
above receptor type is usually found on tripartite
synapses (Fig. 3). The tripartite synapse is an area
that not only involves presynaptic and postsynaptic
neuronal regions, but also is connected to nearby-
located astrocytes. The synaptic NMDA (sNMDA)
receptors are known to be activated by synaptic
glutamate discharge and are neuroprotective in
their nature, as they regulate neuronal survival
[32]. In sNMDA receptors, the NR2A subunits are
activated; such activation further provides anti­
oxidant and antiapoptotic functions. Moreover,
these receptors enhance neuronal survival through
upregulating the neurotrophic factors. At the same
time, extrasynaptic NMDA (eNMDA)-dependent
activation of NR2B subunits regulates actions
opposite to those of NR2A ones [31]. The NR2B
subunits upregulate the excitotoxicity, apoptosis,
and neuronal cell death. The eNMDA receptors also
interact with calpain, upregulate calpain signaling,
and promote neurotoxicity, as was evidenced in a
number of animal studies [32].
Neurotransmitter Alteration and Therapeutic Strategy in AD
GABA in AD.
γ-Aminobutyric acid (GABA) is, probably, the
most important inhibitory neurotransmitter that
mediates inhibitory signaling through GABA A ,
GABA B, and GABA C receptors [33]. The GABA A
and GABA C receptors are ligand-gated chloride
ion channels, while the GABA B receptors are
metabotropic ones, which function via G-protein
coupling. The GABA A receptors consist of two α,
two β, and one γ subunits and are distributed widely
in the brain. The GABA C receptors are formed by
α subunits 1-3 and found to be localized in the retina.
The GABA B receptors are GPC ones functioning
through Gi/Go protein either by inhibiting Ca 2+
channels or by opening K + channels [34].
The role of GABAergic receptors is implicated
in various neurodegenerative disorders, as GABA
controls neurotransmission via the respective
inhibitory mechanism. Various research studies
of AD have reported that reduction in the GABA
levels is observed in this case in the temporal,
parahippocampal, and cingulate cortical regions,
amygdala, putamen, hypothalamus, and nucl.
accumbens, [35]. Some studies have also shown
contradictory results; it was emphasized that GABA
neurotransmission in the brain is not significantly
altered in AD [36]. Transgenic mice studies (for
4-month-old tgCRND8 and 18-month-old APP/PS-1
strains, respectively) showed that there was initial
elevation in GABA and glutamate release, while,
F i g. 4. NMDA and GABA signalling in the earlier and late onset of AD.
299
later on, a decline in such release in age-associated
AD was observed. Some research evidence indicated
that Aβ-induced neuronal pore formation enhances
calcium release in hippocampal neuronal cultures;
this leads to enhanced excitotoxicity and, finally,
neuronal death. : During this, there was initial
NMDA activation, which provoked the action on
postsynaptic GABA A receptors. An increase in
GABAergic neurotransmission could interfere with
the synaptic function and cause a deficit in long-
term potentiation (LTP) in the dentate gyrus, which
could be reversed by picrotoxin [34]. On the other
hand, hippocampal astrocytes release GABA and
glutamate through bestrophin-1(Best-1); these
effects per se were observed to be suppressed
in AD [37]. An increased LTP within early AD
stages produces cognition deficits via action on the
dentate gyrus. Similarly, an enhanced astrocytic
GABA-dependent LTP deficit in the dentate gyrus
is a possible biomarker of AD [38]. However, a
lipoprotein, APOE-4, secreted from GABAergic
neurons disrupts GABAergic neuronal functioning
and impairs cognitive functions [34].
An adequate balance between GABAergic and
glutamatergic neurotransmission is necessary
for normal neuronal functioning. The enhanced
excitotoxicity mediates degradation of GABA B
subunits and reduces expression of these receptors
in late stages of AD. The GABA B receptors consist
of GABA B 1 and GABA B 2 subunits that become
300
phosphorylated by the calcium-calmodulin complex
on ser867 and ser783 residues, respectively,
through NMDA activation [39]. This will lead
to endocytosis of GABA B receptors through
lysosoma-mediated degradation observed in both
hippocampal and cortical cultured neurons (Fig. 4).
However, observations regarding NMDA receptors
are controversial because activation of synaptic
NMDARs exerts neuroprotective action, while
extrasynaptic NMDA Rs provide neurotoxic effects.
Synaptic NMDA Rs mediate long-term potentiation
in AD, and their activation increases expression of
GABA B Rs that act opposite to the extrasynaptic
NMDA receptors [40].
Serotonin in AD.
Mounting evidence has accumulated indicating
that serotonin regulates, to a significant extent,
mood, emotions, sleep/wake cycle, locomotion, and
other behavioral phenomena. Serotoninergic neurons
localized in the raphe nuclei regulate a variety of
functions through various serotoninergic receptors.
There are seven different types of serotonin (5-HT)
receptors present in the brain [41]. The 5-HT1A
receptors have been found to be localized pre-
synaptically and post-synaptically throughout the
brain. The pathways of these receptors connect
the hippocampus with the raphe nuclei and limbic
structures. Cortical pyramidal neurons, GABAergic
neurons, and granular neurons of the hippocampus
are specifically enriched with 5-HT1A receptors
[42]. Administration of a 5-HT1A receptor agonist
modulates theta waves in the hippocampus, and
this fact emphasizes the role of GABAergic septo-
hippocampal connections in memory formation
[43]. Activation of 5-HT1A receptors produces
hyperpolarization in postsynaptic units and
decreases cAMP formation, which inhibits calcium
channel opening. To understand the role of 5-HT1A
receptors in learning and memory, various genetic
models were used, and preclinical studies have been
performed. The genetic knockout model with respect
to 5-HT1A receptors showed noticeable impairment
of spatial learning and memory associated with
hippocampal functions in AD.
Administration of the HT1A receptor agonist
8-hyd­r oxy-2-(di-n-propylamino)tetralin (8-OH-­
DPAT) introduced in different regions of the brain
was shown to improve memory. Similarly, localized
administration by intraseptal infusions caused the
impairment of memory, while dorsal raphe infusion
gave no effect on memory. Furthermore, infusion
to the medial raphe also improved memory, while
S. Kaur et al.
that to the dorsal hippocampus caused mild memory
impairment [42]. Buspirone is another 5-HT1A
receptor agonist; its administration along with
8-OH-DPAT enhanced spatial memory better than
isolated administrations of the above drugs [44]. In
another study, parachlorophenylalanine (PCPA) was
used, which inhibits tryptophan hydroxylase and
reduces 5-HT synthesis. Administration of PCPA
impaired spatial memory, which could be reversed by
an agonist (like flexinoxan). These studies justified
the role of 5-HT1A in the formation of spatial
memory. Activation of 5-HT1B receptors decreased
serotonin release and was associated with changes
in emotional memory and some other functions.
It was also reported that 5-HT1B receptors also
affect the release of other neurotransmitters, like
dopamine and GABA. Post-mortem examinations
of AD patients showed that reduced expression of
5-HT1B receptors in the frontal and temporal cortex
correlated with cognitive and behavioral changes.
Treatment with selective serotonin reuptake
inhibitors (SSRIs), like sertraline, to APP transgenic
mice enhanced the mRNA expression of 5-HT1B
receptors; this was also confirmed in the available
AD studies [45]. The above transgenic study proved
that SSRIs could be reliable antidepressants in AD.
The expression of 5-HT2A receptors was found
to be localized in the neocortex, hippocampus,
entorhinal cortex, limbic system, striatum, olfactory
bulb, hypothalamus, amygdala, and basal ganglia.
Systemic administration of the 5-HT2A selective
agonist TSB-2 improved exploration of a novel
object and formation of fear-associated memory in
rats; this is indicative of the role of this receptor
type in fear-associated and consolidated memory
[46]. Another study [47] revealed that activation
of 5-HT2A receptors on hippocampal neurons
modulates glutamatergic neurotransmission for
memory consolidation. This effect may arise due to
increase in the intracellular Ca 2+ level via 5-HT2A
receptors, which facilitates the functioning of
NMDA receptors and modulates synaptic plasticity.
The decreased expression of 5-HT2A receptors in
neocortical (temporal in particular), regions caused
mild cognitive impairment and long-term memory
loss [48]. Local injections of amyloid-β in the
hippocampus reduced the expression of 5-HT2ARs
in AD model studies [49]. The genetic deletion
of 5-HT2B receptors also affected the learning
and memory impairments in the AD mice model
[50]. Likewise, administration of the 5-HT2B/2C
receptor antagonist (SB221284) impaired learning
Neurotransmitter Alteration and Therapeutic Strategy in AD
and memory, and such effects could be corrected by
selective agonists, like fluoxetine and paroxetine
[51] (Fig. 5).
The 5-HT4 receptors are specifically localized
in the hippocampus; those are associated with
learning and memory formation [52]. These
receptors regulate the neuronal excitability via
changing adenylate cyclase activity, improving
synaptic plasticity through the Src/ERK pathway,
and potentiating neurogenesis and neuronal survival
by modulation of the expression of CREB, Akt, and
BDNF in neurons [53]. The 5-HT4 receptors also
reduce amyloid β accumulation through a non-
amyloidogenic pathway by increasing the activity
of α-secretase and γ-secretase. Activation of 5-HT4
receptors was reported to regulate the release
of ACh, GABA, and dopamine through indirect
mechanisms [52].
Furthermore, available studies indicated that
5-HT6 receptors are involved in memory formation,
which led us to know their functions in cognition and
memory. These receptors are localized more in the
dorsal hippocampus, entorhinal cortex, and striatum
but lesser in the amygdala, substantia nigra, and
several diencephalic nuclei. The 5-HT6 receptors
usually couple to Gs and enhance adenylate cyclase
activity, but certain reports indicated that these
receptors work through Gi and Gq coupling and
contribute to neurotoxicity. The possible mechanism
F i g. 5. Signalling mechanisms and roles of 5-HT4, 5-HT6, and 5-HT-7 receptors in AD.
301
seems to be interaction of the 5-HT6 receptors with
Fyn protein kinase, which activates ERK-1/2 and
enhances tau phosphorylation in AD [54]. These
data are supported by experimental observations;
a specific agonist of for 5-HT6 receptors,
EMD386088, potentiated cell death in neuronal
cell cultures, while a specific 5-HT6 receptor
antagonist, SB258585, moderated cell death by
increasing the intracellular Ca 2+ release [55]. The
5-HT7 receptors are localized in the hypothalamus,
thalamus, hippocampus, cerebral cortex, and raphe
nuclei. Activation of 5-HT7 receptors results in
coupling to Gsα, increases the release of сAMP,
and leads to increased neuronal excitability [56].
This mechanism causes pKa activation, which
results in phosphorylation of CREB, in such a way
contributing to memory consolidation. The 5-HT7
receptors are also coupled to G11/12. This activates
Rho kinase and mitogen-activating protein (MAP)
responsible for neuronal survival and differentiation.
The Rho protein, through activation of its subunit
RhoBTB3, prevents degradation of 5-HT3 receptors,
which is directly linked to the formation of working
memory and self-control [57].
Noradrenaline in AD.
In the brain, noradrenergic neurons are prin­
cipally localized in the locus coeruleus (LC); they
are mostly responsible for the regulation of fight/
flight-like reactions, by affecting arousal, stress,
302
anxiety, executive control, and anger in humans
[58]. The LC sends its noradrenergic projections
towards different regions of the brain, including the
thalamus, hypothalamus, cerebral cortex, amygdala,
and hippocampus [59]. The LC regulates the release
of epinephrine, norepinephrine, and dopamine
from presynaptic nerve terminals after binding to
adrenergic receptors (α, β) for their action. These
neurotransmitters are degraded by certain enzymes,
like catechol-O-methyltransferase (COMT) and
monoamine oxidase (MAO), or can be reuptaken
via the Na/K pump again to the synapses. Their
activity is upregulated in AD [58]. It was revealed
that tau-related pathology is associated with
AD-related neurodegeneration in the LC [60]. It was
hypothesized in the 1990s that parallel activation of
the LC along with that of the peripheral nervous
system is manifested as increased attention and
vigilance due to the animal’s usual cognition towards
any aversion stimulus [58]. Further, the respective
data were supported by the evidence gained from
the Korsakoff ’s syndrome; in this pathology,
death of noradrenergic neurons and depletion of
norepinephrine (NE) metabolites in the cerebral
fluid are observed. The Korsakoff’s syndrome is a
memory-oriented problem occurring due to chronic
consumption of alcohol and malnutrition [61]. This
example greatly emphasizes the importance of
the NE system in memory and cognition. In a few
F i g. 6. Involvement of the amygdala and hypothalamus and amyloid protein formation in AD.
S. Kaur et al.
studies, the significant role of NE-ergic LC neurons
in the latter phenomena (memory and cognition) was
emphasized [62, 63].
DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromo­
benzylamine hydrochloride) is a selective neurotoxin
for NE neurons, and its administration in the brain
leads to destruction of memory [62]. This memory
disturbance gets more severe along with depletion
of dopamine and acetylcholine. The increase in the
NE level was shown to improve spatial memory and
recognition memory, which was demonstrated in
the radial arm maze test and object recognition test,
respectively.
The amyloid β processing and synthesis not only
occur in the hippocampus but are also found in
chromaffin cells of catecholaminergic neurons, as
was reported by a few in vitro studies. Stimulation of
chromaffin cells by KCl induced the depolarization
enhancement and release of Aβ along with NE [63].
This is explained as follows: these events include
activation of α 2 and β 2 adrenergic receptors present
on synaptic terminals of the LC [64, 65]. There
are only some studies reporting that an increase
in the number of α 2 ARs in the frontal cortex and
hippocampus is related to polymorphism of the
gene encoding α 2ARs. These receptors regulate the
synthesis and production of Aβ, which was shown
in transgenic studies by interacting with SorLA-like
APP trafficking protein [64]. The β 2ARs are capable
Neurotransmitter Alteration and Therapeutic Strategy in AD
of directly regulating the activity of the γ-secretase
complex and enhancing Aβ production in AD; this
receptor type was found to decrease Aβ production
in transgenic mice [65].
Remarkably, there is another reliable explanation
regarding damage to the LC in the AD brain. The
LC role in memory formation is regulated by
some projections oriented to the amygdala and
hypothalamus. The amygdalar projections provide
intensification of the production of corticotrophin
releasing factor; the latter acts as a stressor for the
LC. Similarly, the hypothalamic projections regulate
glucocorticoid and hypocretin (orexin) signaling
that mediate the release of NE in the LC [66, 67]
(Fig. 6).
Some evidence indicates that basolateral amyg­
dala-dependent activation of β2ARs regulates the
LC functioning under conditions of the formation
of fear-associated memory [66]. The hypothalamic
glucocorticoid and corticosterone projections to the
LC regulate memory consolidation in response to
stress. The production of both glucocorticoids and
corticosterone is upregulated in stress situations,
and this was reported to enhance the amyloid β
production in AD [67]. Hypothalamus-mediated
projections regulate orexin signaling and balance
the sleep-wake cycle that is strongly dysregulated in
AD. Administration of an orexin receptor antagonist
not only balances the disturbed sleep-wake cycle,
but also decreases the amyloid β load in AD
[68, 69]. Thus, neurodegeneration occurring in the
LC contributes to both cognitive and noncognitive
impairments in AD patients.
Endocannabinoids in AD.
Endocannabinoids are relatively newly iden­tified
neurohormones synthesized locally and released
in various regions of the CNS. Unlike most other
neurochemical agents, endocannabinoids belong
to the lipid-mediated eicosanoid family derived
from degradation of phospholipids. The most
common endogenous cannabinoids are arachi­­do­n o­
ylethanolamine (AEA, or anandamide), 2-arachi­
donoylglycerol (2-AG), and others (2-arachi­
donylglyceryl ether (2-AGE), virodhamine, and
N-arachi­d onyldopamine). The discovery of endocan­
nabinoids is attributed to the ancient use of the
Cannabis plant, which retains specific actions on the
CNS mostly due to the presence of a psychoactive
constituent named 9∆-tetrahydrocannabinol (9∆-
THC) [70]. Endocannabinoid receptors (CB-1 and
CB-2 Rs) are widely distributed in the CNS and
303
involved in the mediation of a variety of functions
like cognition, memory, emotions, and pain
perception. The CB1 receptors are present in the
hippocampus, cortex, basal ganglia, and cerebellum.
These receptors were reported to be localized on
excitatory and inhibitory presynaptic terminals
and postsynaptic structures [71]. CB2 receptors are
rarely found in the healthy brain, but their number is
increased in astrocytes and microglia upon damage
and/or with aging.
The exact role of endocannabinoids signaling in
the AD is still under study. It was reported that the
CB1 receptors are either depleted [72] or seemed
to be unaltered in the hippocampus and cerebral
cortex of AD patients [73]. However, the expression
of CB2 receptors in microglia has been reported to
be enhanced at amyloid β aggregation in the brain,
which may be a protective endogenous phenomenon
within the initial AD stage [74]. Administration
of endogenous endocannabinoids to neuronal
cell cultures after exposure to toxic Aβ species
enhances the viability of neurons in in vitro AD
studies. Simultaneously, exogenous cannabinoids
were shown to increase neuronal survival in AD.
Results of in vitro and in vivo studies gave reasons
to believe that a cannabinoid agonist cannot only
reduce amyloid β aggregation, but also enhance
its clearance through the blood-brain barrier [75,
76]. A selective CB1 receptor agonist reduced tau
hyperphosphorylation via decreasing GSK-3β, p-38,
and JNK activity [77]. This agent was not only
beneficial against specific protein aggregation, but
was also proven to relatively normalize the neuro­
trans­m ission processes in AD. A cannabinoid,
9∆-THC, was reported to competitively inhibit
the acetylcho­linesterase enzyme and enhance cho­
linergic neurotransmission in AD. A synthetic
cannabinoid, HU-211, selectively inhibited NMDA-
induced excitotoxicity in AD [78]. Moreover,
numerous studies indicated that cannabinoid
signaling is protective against neuroinflammation,
mitochondrial damage, oxidative stress, and
neurodegeneration in this pathology. Similarly,
cannabinoid signaling in GABAergic neurons
protects the brain against a cognitive decline by
regulating long-term potentiation-related memory
[70].
Drugs Targeting Neurotransmitters in the
Preclinical and Clinical Phases of AD.
To bridge neurochemistry-targeting drugs in
AD, we examined various clinical and preclinical
304
study reports. A recent study [79] reported that
about 23% of the drugs targeting neurotransmitters
have been tested in AD-related clinical trials up to
2017. This number is the highest among the other
probable mechanisms related to the treatment of
this pathology (like anti-tau therapy, anti-amyloid β
therapy, and metabolic drugs) [79]. The summarized
data include not only drugs reaching the stage of
immediate clinical trials, but also neurotransmitter-
targeting drugs used in preclinical studies (Fig. 7).
The list of the preclinically tested compounds
is too long and wide, because a great number of
mo­ l ecules are being evaluated for their better
efficacy as neuroprotective means in AD (Fig. 8).
Upregulation of the cholinergic system by
flavonoids and carbamate derivatives is still
under investigation through in silico, in vitro, and
in vivo studies. Flavonoids, like rutin, myricetin,
quercetin, kaemferol, and macluraxanthone, were
evaluated for their effectiveness in inhibiting the
acetylcholinesterase enzyme in AD. Agonists of M1
muscarinic receptors, like AF102B, AF267B, AF150,
and AF292B, were shown to be useful neuroprotective
agents in various AD studies. Other molecules,
F i g. 7. Drugs targeting different neurotransmitters, which have been tested in clinical evaluation as therapeutic means in AD.
S. Kaur et al.
like 77-LH-28-1, VU0357017, and VU364572,
were reported to have a better M 1 selectivity and
permeability in the brain [80]. Most M1 agonists failed
to demonstrate sufficient success during clinical trials,
and this led to the focusing attention on nicotinic
agonists like, EVP-6124. These agents demonstrated
reliable efficacy in AD studies [80]. Excitatory
neurotransmission studies have already focused
on memantine-like drugs, whose efficacy has been
clinically approved. The other targeting molecules
include MK-801(an NMDA-blocking agent),
huperzine-A, neramexane (an uncompetitive NMDA
antagonist), ifenprodil (a GluN2B antagonist), and RO
25-6981 (a GluN2B antagonist); these drugs showed a
reliable efficacy over excitatory neurotransmission in
AD studies [31]. Inhibitory neurotransmission plays
a controversial role in AD because both “agonist”
and “antagonist” studies reported in the literature
gave rather contradictory results. The GABA A ago­
nists (etazolate, muscimol, propofol, MRK-016,
CGS9896, Ro-4938581, and Ro-4882224) and
GABA B antagonists (SGS742 and CGP55845) were
reported to improve cognition and memory in the
respective studies [34].
Neurotransmitter Alteration and Therapeutic Strategy in AD
One recent report [20] revealed the role of
dopamine in the modulation of hippocampal memory
and synaptic plasticity through administration
of dopamine supplements (like levodopa) and
monoamine oxidase-B inhibitors (like selegiline).
The expression of MAO mRNA was found to
increase in the brain of AD patients. Polymorphism
of certain MAO-related genes was also reported
in the brain of such patients. Earlier, it was shown
that MAO-A activity is upregulated in AD, but the
interaction of MAO-B with presenilin emphasizes
the role of the latter enzyme subtype in amyloid β
processing. Administration of an MAO-B inhibitor,
selegiline, helped to reverse the amyloid β pathology
and cognition loss in transgenic animal studies.
Catechol-O-methyltransferase (COMT) is another
enzyme responsible for dopamine degradation, and
its expression was found to increase after brain
injury, trauma, and lipopolysacharide injections;
so, the role of the above enzyme in AD-related
machinery cannot be ruled out. Another drug is
L-DOPS (droxidopa), which is expected to reverse
F i g. 8. Drugs targeting different neurotransmitters, which have been tested in preclinical evaluation as therapeutic means in AD.
305
the spatial deficits induced by LC degeneration
and was shown to be protective over NA neuronal
loss in AD. A number of drugs, like vindeburnol,
allopregnenolone, sertraline (SSRI), venlaflaxine
(SNRI), desipramine, and atomoxetine (NARI),
were implemented in various AD studies and have
shown some good results for neuroprotection and
over cognition loss [81]. Recently, cannabinoids
have attracted much greater attention in the
search of therapeutic agents in AD. Endogenous
cannabinoids (dronabinol, AEA, 2-AG, and noladin
ether) added to amyloid β-treated cells enhanced
neuronal survival and decreased amyloid β overload
in in vitro studies [77]. Similarly, arachidonyl-2-
chloroethylamide (ACEA), CB2 selective agonists
(JWH-015 and JWH-133), and mixed CB1/CB2
receptor agonists (9-THC, HU-210, and WIN55,
212-2) were shown to be neuroprotective agents
in various AD studies [82]. HU-210 is a synthetic
cannabinoid capable of reducing excitotoxicity via
direct binding to NMDA receptors, which makes it
a reliable agent in AD research [78].
306
Thus, it should be recognized that there are
numbers of loopholes regarding the pathogenesis
of AD. In the current review, the role of various
neurotransmitters has been discussed on the
basis of their receptor mechanisms behind their
contribution in pathophysiological signaling in
AD. Targeting the cholinergic system could be a
rational approach to halt AD development. At the
same time, other neurochemicals, like dopamine,
GABA, glutamate, and endocannabinoids, are
involved in the modulation of memory, cognition,
and neurodegeneration in AD and its models; thus,
different aspects of the respective phenomena
should be examined. There is a need to look at the
possible hidden mechanisms and multidrug therapy
for AD treatment. Further studies are required to
explore the immune- and genetic-based alterations
in the neurotransmitter levels in AD patients. So,
to overcome these neurological problems, targeting
neurotransmitters, agents suppressing hyper-
immune responses, and those altering enzyme
levels may be useful to devise superior remedies,
which could minimize symptoms and elucidate AD
pathophysiology.
Acknowledgment. We are highly thankful to the chairman
of the ISF College of Pharmacy, Moga, Punjab, India, for
providing a favorable educational and research environment.
This paper is a review of the available literature; so,
special confirmation of its correspondence to the existing
ethical standards for the experimental studies is not
necessary.
The authors, S. Kaur, G. DasGupta, and S. Singh, declare
the absence of any conflict in commercial or financial
relations, relationships with organizations or persons
that in any way could be related to the study, and also in
interrelations of the co-authors.
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