Stress-Induced Synaptic Dysfunction and Neurotransmitter Release in Alzheimer’s Disease: Can Neurotransmitters and Neuromodulators be Potential Therapeutic Targets?

Abstract

The communication between neurons at synaptic junctions is an intriguing process that monitors the transmission of various electro-chemical signals in the central nervous system. Albeit any aberration in the mechanisms associated with transmission of these signals leads to loss of synaptic contacts in both the neocortex and hippocampus thereby causing insidious cognitive decline and memory dysfunction. Compelling evidence suggests that soluble amyloid-β (Aβ) and hyperphosphorylated tau serve as toxins in the dysfunction of synaptic plasticity and aberrant neurotransmitter (NT) release at synapses consequently causing a cognitive decline in Alzheimer’s disease (AD). Further, an imbalance between excitatory and inhibitory neurotransmission systems induced by impaired redox signaling and altered mitochondrial integrity is also amenable for such abnormalities. Defective NT release at the synaptic junction causes several detrimental effects associated with altered activity of synaptic proteins, transcription factors, Ca²⁺ homeostasis, and other molecules critical for neuronal plasticity. These detrimental effects further disrupt the normal homeostasis of neuronal cells and thereby causing synaptic loss. Moreover, the precise mechanistic role played by impaired NTs and neuromodulators (NMs) and altered redox signaling in synaptic dysfunction remains mysterious, and their possible interlink still needs to be investigated. Therefore, this review elucidates the intricate role played by both defective NTs/NMs and altered redox signaling in synaptopathy. Further, the involvement of numerous pharmacological approaches to compensate neurotransmission imbalance has also been discussed, which may be considered as a potential therapeutic approach in synaptopathy associated with AD.

Keywords

Amyloid-β neurotransmitters/neuromodulators redox signaling synaptic dysfunction tau therapeutics

INTRODUCTION

To maintain brain homeostasis, synapses and their associated neurotransmitters (NTs) play the role where synapses are specialized structures that form a network to transmit electrochemical signalsor information from one neuron to another. The signal transmission involves a complex process of NT release and uptake at synaptic junctions [1] where dysregulation of the synaptic junction in response to numerous insults and aberrant NT releases or its receptors lead to synaptopathy associated with Alzheimer’s disease (AD) [2]. It has been demonstrated that soluble amyloid plaques and hyperphosphorylated tau served as toxins in disrupting synaptic plasticity and NT release at synapses, thereby causing a cognitive decline in AD [3, 4]. In addition, free radicals, oxidative stress, and mitochondrial dysfunctions have also contributed significantly toward synaptic loss [5]. Redox signaling has also been shown to alter the signaling cascades associated with the pathophysiology of synaptic loss and thus cause vulnerability to neuronal cells in AD [6]. Since the exact mechanisms associated with synaptic dysfunction induced by impaired NTs and altered redox signaling remain enigmatic, their plausible association is under investigation. In this regard, the present review underlines the involvement of both defective NTs and altered redox signaling in the etiology of synaptic loss associated with AD, and also demonstrates the involvement of numerous biological compounds and recent therapeutic strategies for targeting synaptic loss induced by defective NTs and neuromodulators (NMs).

SYNAPTOPATHY IN ALZHEIMER’S DISEASE: CORRELATION BETWEEN SYMPTOMS AND SYNAPTIC FAILURE

Synapses are an alliance of specialized structures that allow a neuron to pass a chemical or an electrical signal to another neuron. This electro-chemical transmission is a complex interplay among NT release at presynaptic terminals and its detection at receptors of postsynaptic terminals of a neuron [7, 8]. While any dysregulation in synaptic transmission leads to a number of chronic brain disorders, including addiction, depression, anxiety, and dementia like AD and Parkinson’s disease [9]. There is numerous evidence depicting the promising role of synaptic plasticity in memory formation and its stabilization. Recent methodological advancements have uncovered the mystery behind synaptopathy and its consequent dysregulation in neural circuitry [10]. For instance, amyloid-β (Aβ) and tau proteins were reported to function normally at synaptic junctions while their overburden caused neuronal toxicity and thus synaptic loss in the case of AD [11]. Hyperphosphorylated and aggregated forms of tau are leading agents for synaptic dysfunction, behavioral impairment, and neuronal death in neurodegenerative disorders (NDDs) [12]. It is reported to directly interact with postsynaptic signaling complexes to regulate synaptic transmission [13]. On the other hand, major kinases such as glycogen synthase-3β (GSK3β), cyclic adenosine monophosphate response element-binding protein (CREB), extracellular receptor kinase (ERK), and mitogen-activated protein kinase (MAPK) are found to induce synaptic dysfunction through their dynamic association with stress-mediated abnormal hyperphosphorylated or accumulated forms of tau in the AD brain [5]. Recently, abnormal acetylation at K281 and K274 of tau protein has been reported to promote synaptic loss in the AD brain viz. reduction of AMPA receptors trafficking, damaged actin dynamics, and diminished postsynaptic KIdney/BRAin (KIBRA) signaling pathways [14]. Additionally, several groups demonstrated the pathogenic role of soluble Aβ in dendritic spine injury in cultured neurons, while its monomeric and fibrillar forms remained inert to synaptic loss [15]. The available evidence suggests that abnormally acetylated and phosphorylated forms of tau, aggregated forms of Aβ, and impaired synaptic plasticity are the key components involved in the synaptopathy of AD [16]. Unlike Aβ and tau, various other factors have also been identified to cause synaptic dysfunction in AD (Table 1). These factors significantly affect neurotransmission and correlate with the disease symptoms including cognitive decline and dementia in AD.

Table 1

Causative factors and associated mechanisms of synaptic dysfunction in AD

SN	Causative Factors	Associated Mechanisms (Synaptic Dysfunctions)	Disease Involved	References
1	Factors associated with oxidative stress and mitochondrial dysfunction	Causes apoptotic cell death and elevation of caspase-3 activity associated with enhanced level of long-term depression (LTD), which further leads to synaptic loss		[17]
2	Ca²⁺ dyshomeostasis	Affects calcineurin (CaN) activity that causes alteration in N-methyl-D-aspartate (NMDA) receptor activity and impairment of long-term potentiation (LTP), leading to synaptic loss		[18]
3	Cholesterol and lipid depletion	Induces formation of protein aggregates that leads to the impairment of both NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which further affects glutamate transmission, alters the LTP and synaptic loss		[19]
4	Factors associated with inhibition of protein phosphatases	Increases cytoskeletal protein phosphorylation which further induces Ca²⁺ dyshomeostasis and glutamate excitotoxicity, thereby leading to loss of synaptic activity in the brain		[20]
5	STEP₆₁	Increased activity of STEP₆₁ causes inactivation of ERK1/2 signaling and alteration in NMDA receptor		[21]
6	MAPK phosphatases	Inactivate Mitogen-activated protein kinases (MAPK) and cause neuronal excitability and synaptic dysfunction		[22]
7	Dyshomeostasis of Fe²⁺, Cu²⁺, Zn²⁺ and other metal ions	Causes alteration in glutamate activity and modulates various ionotropic, metabotropic, and postsynaptic receptors such as NMDA and AMPA receptors		[23]
8	Factors associated with microglial dysfunction	Induces the release of proinflammatory cytokines such as IL-1β, TNFα, and TNFR1, thus causes apoptosis. Moreover, it also causes alteration in the AMPA receptors at the synapse	Alzheimer’s disease	[24]
9	GABAergic and Glutamatergic excitotoxicity	Causes alteration in Ca²⁺ homeostasis, involved in the modulation of various receptors such as NMDA and AMPA, and also responsible for the production of free radicals thereby leading to apoptosis of neuronal cells		[4, 25]
10	Glutamate transporter 1 (GLT1)	Dysfunction of GLT1 causes excessive glutamate release and impairment of NMDA and AMPA receptors		[26]
11	Mutations in AβPP/PS1	Causes alteration in stathmin signaling, 14-3-3-mediated signaling, CREB signaling, and protein kinase A (PKA) mediated signaling pathways. Further, it also alters the activity of both NMDA receptor and glutamate release		[27]
12	Aβ	Alters acetylcholine, NMDA, and AMPA receptor activity. It also affects Wnt signaling pathway and causes alteration in glutamate, norepinephrine, and GABA release that further leads to the accumulation of tau at postsynaptic terminals		[28 –30]
13	Tau	Mislocalization of hyperphosphorylated tau in dendritic spines causes both the disruption of glutamate receptor and Aβ-related synaptic excitotoxicity		[31]
14	GirK Channels	Aβ interferes with GirK channels, curtailing LTP and increasing LTD, thereby mediating synaptic dysfunction		[32]
15	IGF-1 depletion	Causes defects in both LTP and LTD and augments incorporation of glutamate receptors through the activation of PI3K/Akt signaling		[33]
16	ApoE4	Affects PKA, calcineurin, BDNF, and CREB mediated signaling pathways thereby leading to synaptic loss		[34]

THE PERTINENT ROLE OF AMYLOID-β IN SYNAPTIC BIOLOGY OF ALZHEIMER’S DISEASE

Aβ is a prevalent toxic protein deposited as senile plaques and is likely to be involved in the impairment of synaptic plasticity in both sporadic and familiar forms of AD [35]. One and foremost among the numerous proposed mechanisms associated with Aβ-mediated synaptic dysfunction is toxicity due to its self-aggregation and interaction with various other membranous proteins at synaptic junctions [36]. Importantly, Aβ is found to moderately terminate mGluR-dependent synaptic long-term depression (LTD), thereby signifying its role in modulating synaptic plasticity [37]. Growing evidence suggests that Aβ oligomers also interact with various NTs/NMs to inhibit synaptic transmission by dysregulation of these receptors. For instance, glutamatergic, GABAergic, and serotoninergic receptors were observed with compromised expression at neuronal synaptic junctions [38, 39]. Similarly, Aβ oligomers interacted with a dozen receptors to trigger the distribution of critical synapticproteins and induce hyperactivity in ionotropic and metabotropic glutamate receptors [40]. Likewise, there is evidence indicating the interaction of Aβ oligomers with glutamatergic receptors to either facilitate or inhibit the uptake of glutamate and thus cause Aβ-mediated synaptic loss [26]. Moreover, glutamatergic receptors (AMPA and NMDA) are found to regulate Aβ-mediated synaptic dysfunctionvia aberrant redox signaling and cytoplasmic Ca²⁺ overload, which triggers downstream pathways including protein phosphatase 2A (PP2A) and Ca²⁺ dependent protein phosphatase calcineurin/PP2B [39]. Additionally, NMDA receptors insults are also found to promote the amyloidogenic processing of amyloid-β protein precursor (AβPP) to induce oligomeric Aβ production and trigger synaptic failure and memory loss [41]. Multiple studies also revealed that Aβ causes neuroinflammation via activation of microglial cells and alters the level of ERK, CaMII, and pCREB to impair long-term potentiation (LTP) and LTD. Such alterations trigger a negative feedback mechanism to deplete the regulation of GSK3β and consequent abnormal Aβ and oligomeric tau production at synapses leading to synaptic dysfunction and memory impairment [42 –44]. Besides, numerous studies on hippocampal neurons explored the effects of Aβ and human amylin on LTP with the expression of amylin receptors, while its blockade led to LTP enhancement in transgenic mice to trigger Aβ burden in brain [45]. In this way, multi-disciplinary research has been carried out extensively that identified potential receptors involved in synaptic loss, which could be potential targets for therapeutic intervention.

TAU PROTEIN AS A CULPRIT OF SYNAPTOPATHY IN ALZHEIMER’S DISEASE

Tau protein is another significant pathological hallmark of AD in its hyperphosphorylated form as neurofibrillary tangles (NFTs) and is associated with cognitive decline, memory impairment, synaptic dysfunction, and neuronal loss [46]. Nevertheless, tau phosphorylation is also known for synaptic plasticity during the early stages of neuronal development, but it declines with the aging brain [47]. However, NFTs are reported in varying degrees in the brain before the onset and throughout the progression of AD, but it was not proportionate with the neuronal death. Even the neuronal death exceeded the amount of NFTs indicating that it is not a prominent cause for neuronal death [48]. Furthermore, researchers revealed that it is not the number of NFTs that are responsible for dementia, but it is the aggregated form of tau at synaptic junctions that causes synaptic dysfunction and is vulnerable to neurons [46]. Recent evidence showed that tau-mediated memory impairment is partly associated with decreased RNA translation, due to very close association of ribosomes with tau proteins in AD with respect to control brains [49]. Another study identified that impaired synthesis of postsynaptic density protein-95 (PSD-95) contributes toward the decline of synaptic plasticity that is crucial for learning and memory [50]. Similarly, earlier studies on human fetal cerebral cortical neurons reported the association of an aberrant rise in Ca²⁺ levels with tau hyperphosphorylation leading to microtubular degeneration in AD [51]. Further, chronic exposure of inorganic Arsenic compounds (iAs) and its metabolites facilitated tau hyperphosphorylation and increased AβPP expression. Besides, it also causes altered NT synthesis, increased glutamate receptors activation, and reduced glutamate transporters expression, thereby affecting synaptic transmission [52]. A study demonstrated the increase in accumulation of phosphorylated tau that triggered synaptic loss, neurite retraction, Ca²⁺ dyshomeostasis, and altered NT release (reduced acetylcholine (ACh) levels) in tau oligomer treated neurons [53]. Tau phosphorylation is also modulated by Bcl2 Associated Athanogene-2 (BAG2) expression, since it controls a functional intracellular switch between the p38-dependent functions of nicotine on tau phosphorylation levels via the α7 nicotinic receptor [54]. Furthermore, glucocorticoid (GC, stress hormones) mediated synaptic loss has been evident in AD models via tau hyperphosphorylation, missorting, and mislocation [55, 56]. Recently, abnormal acetylation of K274 and K281 sites on tau has been reported to stimulate disruption of synaptic plasticity and memory by reducing postsynaptic KIBRA (a memory-associated protein) in transgenic mice [14]. Interestingly, another variant of human tau A152T (hTau-A152T) is found to increase the risk for synaptic loss by increasing hyperphosphorylated forms of tau protein and by promoting network hyperexcitability that triggered age dependent neuronal loss at synapses in AD [57]. Apart from Aβ and tau, oxidative stress and mitochondrial dysfunction also play a key role in synaptic dysfunction.

HOW OXIDATIVE STRESS LINKED MITOCHONDRIAL DYSFUNCTION IS A CAUSE FOR SYNAPTIC LOSS

Mitochondria possess an extensive role in ATP production, reactive oxygen species (ROS) generation, Ca²⁺ homeostasis, and apoptotic signaling; while being a great source of intracellular ROS, they are mainly vulnerable to oxidative stress [17]. Nowadays, oxidative stress and subsequent damage to mitochondrial integrity has been widely implicated in various NDDs including AD, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and amyotrophic lateral sclerosis [58]. Since neurons are energy dependent on mitochondrial activities for its critical functioning, including axonal/dendritic transport, synaptic transmission, and ion pumps and channels, oxidative stress-mediated mitochondrial damage is the predetermining factor for causing synaptic loss in neurons [59, 60]. Moreover, it has been observed that under extreme conditions of oxidative stress, mitochondrial damage takes place primarily at complex IV (cytochrome oxidase) of the electron transport system [61]. This damage ultimately leads to synaptic loss in association with oxidative alteration of the mitochondrial membrane phospholipid; cardiolipin [62]. Synapse maintenance is a prerequisite for proper communication and therefore, synapses are densely packed with mitochondria in order to fulfill their high-energy demands and Ca²⁺ buffering requirements for synaptic transmission [63]. Moreover, synaptic mitochondria are responsible for clearing Ca²⁺ either directly or by providing ATP to Na⁺/Ca²⁺ exchangers to maintain Ca²⁺ homeostasis in order to govern normal synaptic function [64]. Defective mitochondrial buffering mediated Ca²⁺ overburden causes severe brain tissue injury in response to glutamate excitotoxicity [65]. Likewise, elevated ROS accumulation causes vulnerability to cells in response to compromised shock regulatory proteins and leads to the formation of the mitochondrial permeability transition pore (mPTP). The prolonged opening of mPTP can cause both necrosis and apoptosis via cytochrome C release and consequent activation of caspases [66]. Furthermore, oxidative stress was shown to also contribute significantly toward neuronal damage in the substantia nigra via dopamine-mediated quinone formation [67]. Nevertheless, deficits in axonal transport of mitochondria from soma to distal synapses are prevalent in NDDs. Moreover, some genetic factors have been identified that regulate mitochondrial transport; for instance, PTEN-induced putative kinase 1 (PINK1) is found to interact with Miro and Milton’s protein to govern mitochondrial trafficking and distribution [68]. In another study, perturbed mitochondrial fusion/fission proteins are found to affect dendritic mitochondrial populations thereby affecting synaptic plasticity [69]. Likewise, many compounds and elements have been identified so far, which are responsible for oxidative stress/mitochondrial dysfunction mediated synaptic loss in AD (Table 2). The investigations suggest that synaptic dysfunction is presumably one of the initial events in the majority of NDDs associated with mitochondrial abnormalities or irregular mitochondrial distribution in neurons causing clinical symptoms such as motor dysfunction, cognitive decline, and memory loss.

Table 2

Key compounds and elements involved in oxidative stress/mitochondrial dysfunction mediated synaptopathy

SN	Compounds and Elements	Mechanisms associated with Synaptic Loss	Disease Involved	References
1	Methotrexate (MTX)	MTX treatment increases the levels of phosphorylated tau, AβPP, and β-secretase thereby causing oxidative stress mediated synaptic loss		[70]
2	Okadaic acid (OKA)	It induces neurodegeneration by provoking tau hyperphosphorylation, GSK3β overstimulation, oxidative stress, neuroinflammation, altered neurotransmission, and neurotoxicity. Moreover, it also acts as a selective inhibitor of protein phosphatase, PP1 and PP2A		[71]
3	Acrolein	Acrolein is a peroxidation product of arachidonic acid (AA) that augments tau phosphorylation at the site recognized by PHF-1 thereby causing oxidative stress in primary neuronal cultures		[72]
4	Cocaine	Peritoneal injection of cocaine promotes Alzheimer-like hyperphosphorylation of tau and neurofilaments thereby causing oxidative stress in rat brain. Further, it also increases the levels of dopamine, as does nicotine		[73]
5	Lipopolysaccharide	Lipopolysaccharide treatment causes both synaptic alteration and learning-memory deficit by inducing paired immunoglobulin-like receptor B (PirB) expression		[74]
6	Rotenone	Rotenone treatment causes inhibition of complex I of the electron transport chain (ETC), thus induces cell death of cholinergic neurons	Alzheimer’s disease	[75]
7	Paraquat	Paraquat exposure causes increased oxidative damage specifically in mitochondria of cerebral cortex and manifests mitochondrial dysfunction, thus leads to synaptic loss		[76]
8	1-methyl-4-phenylpyridinium (MPP(+))	Treatment with MPP (+) causes generation of ROS from inhibition of complex I of the mitochondrial respiratory chain and inactivation of aconitase. Further, it also causes ROS-mediated oxidative damage and apoptosis, thereafter lead to synaptic loss		[77]
9	Copper (Cu²⁺)	Chronic exposure of Cu²⁺ causes altered spatial memory with selective loss of synaptic proteins pre-synaptic protein synapsin 1 and post PSD-95 through the mechanisms including activation of PKR/eIF2α signaling pathway		[78]
10	Iron (Fe²⁺)	Fe²⁺ is responsible for triggering synaptic loss and apoptotic cell death by affecting mitochondrial dynamics		[79]
11	Aluminum (Al³⁺)	Al³⁺ exposure decreased the levels of NTs and acetylcholinesterase activity in the brain. Further, it promotes cross-linking of toxic Aβ thereby causing both oxidative stress and synaptic dysfunction		[80]

FREE RADICALS, REACTIVE OXYGEN SPECIES, AND CELL-SIGNALING IN SYNAPTIC DYSFUNCTION

Free radicals are highly reactive chemical species having one or more unpaired electrons, and are generated in the complex I and complex III of mitochondria. The iron-sulfide centers and semiquinone or cytochrome b are believed to be likely candidates for its generation in mitochondrial complex I and III, respectively [81, 82]. The altered ROS homeostasis activates various signaling pathways underlying cell inflammation; for instance, ROS and other reactive species regulate the expression of numerous inflammatory mediators including interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), lipoxygenase (LOX), cycloxygenase-2 (COX-2), and cell adhesion molecules (VCAM-1, ICAM-1, P & E-selectin) [83 –85]. Additionally, ROS has been identified as key modulators of signal transduction cascades pertaining to synaptic plasticity and memory functions without the help of GTPases, phosphatases, protein kinases, Ca²⁺- dependent enzymes, and other transcription/translation factors [86, 87]. For instance, ROS sensitive calcineurin (PP2B) is believed to suppress LTP by inhibiting LTP-inducing kinases CaMKII and PKC. Moreover, ROS exhibits two-fold roles in LTP; one is stimulation and other is inhibition. For example, in rodent hippocampus, superoxide scavenging blocked high frequency stimulated LTP (HFS-LTP), while superoxide dismutase (SOD) mediated H₂O₂ burden caused LTP inhibition [88]. NMDA receptor is another candidate, which is directly attacked by ROS to affect synaptic plasticity and long-term memory formation. Another reactive species, nitric oxide (NO) plays a dual role in neurobiology by provoking both neuroprotection and neurodegeneration. For instance, NO boosts synaptic plasticity by evoking dendritic Ca²⁺ release via ryanodine receptor (RyR) while its aberrant production triggers synaptic loss via enhanced activation of soluble guanylyl cyclase (sGC)/protein kinase G (PKG) pathway and RhoA/Rho kinase (ROCK) signaling pathway [89, 90]. Furthermore, ROS also directly modulates voltage-dependent Ca²⁺ channels and thus altering synaptic transmission. Additionally, the protein RanBP9 is found to elicit ROS production, mitochondrial dysfunction, and Ca²⁺ dysregulation in AD models [91]. Accumulating evidence suggests that synaptic loss is also caused by altered insulin signaling pathway. This signaling is triggered via an insulin receptor substrate (IRS) that further interacts with numerous other receptor tyrosine kinases including IGF1/2, tropomyosin-related kinase receptor B (TrkB), and ErbB. The phosphorylation of IRS1 on tyrosine residues thereafter leads to the activation of downstream signaling including, Akt, mTOR, and GSK3. Furthermore, the phosphorylation of IRS1 on multiple serine (Ser) residues inhibits IRS1 activity leading to insulin resistance (IR), which further contributes to both Aβ accumulation and tau phosphorylation associated with synaptic loss (Fig. 1). Most importantly, IR is also accountable for altered insulin degrading enzyme (IDE) and neprilysin (NEP) activity, which is induced by accumulated Aβ in AD [92, 93]. Similarly, ROS-mediated microglial activation induced by toxic Aβ is another cause for both neuroinflammation and synaptic dysfunction in AD. Because, Aβ activated microglia is responsible for synaptic loss by releasing numerous neurotoxic mediators including cytokines, interleukin, and TNF-α that propagate an inflammatorycycle [94]. Furthermore, CREB acts as a central converging point of diverse signaling cascades that are involved in synaptic strengthening and memory formation and is also reported to be altered by Aβ accumulation [95]. Further research is required to determine other important targets of ROS signaling to investigate their significance in synaptic transmission and neuronal homeostasis.

Fig.1

Schematic illustration showing the different signaling axis that is involved in Aβ-induced synaptic dysfunction and its associated factors. ROS, reactive oxygen species; NFTs, neurofibrillary tangles; IDE, insulin-degrading enzyme; NEP, neprilysin; NOS, nitric oxide synthase; NO, nitric oxide; GC, guanylyl cyclase; cGMP, cyclic guanosine monophosphate; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cyclic adenosine monophosphate response element-binding protein; UPS, ubiquitin proteasome system.

NEUROTRANSMITTERS/NEUROMODULATORS: A KEY MEDIATOR OF CELLULAR HOMEOSTASIS OR SYNAPTOPATHY?

NTs are a diverse group of endogenous compounds that act as chemical messengers to transmit the electrical/chemical information throughout the body. Nerve impulses rely on synapses for the release of NTs from presynaptic axons and its detection at postsynaptic terminals [8]. These NTs normally maintain cellular homeostasis via regulation of interdependent elements/chemicals through a number of physiological processes, while its depletion may affect different processes like concentration, mood, sleep, weight, and various others leading to altered cellular homeostasis [96]. For instance, NTs like glutamate, aspartate, GABA, and ACh have been implicated in synaptic dysfunction associated with the progression of AD [4]. The mechanisms underlying synaptic dysfunction are linked to the alteration of their receptors that lead to the pathogenic events in the progression of NDDs. The mechanisms associated with NT/NM-mediated synaptic dysfunction in AD are discussed here.

Acetylcholine

ACh release is responsible for the regulation of memory storage and cognition in cortex and sub-cortical circuits [97]. ACh interacts with two types of receptors; G protein coupled muscarinic acetyl cholinergic receptors (mAChR) and ionotropic nicotinic acetyl cholinergic receptors (nAChR) and triggers distinct responses to different modulators [98]. The α7 nAChR receptors are found to regulate intracellular Ca²⁺ and NT release at synaptic junctions. nAChR are also evident for synaptic plasticity by stimulating the upregulation of LTP in the hippocampus [99]. In fact, the progressive loss of cholinergic signaling is among the major breakdown mechanisms associated with the etiology of AD. For instance, dysfunctional nAChR/mAChR in the cortex resulted in cognitive decline in AD. However, this failure of cholinergic transmission is not merely a loss of ACh containing neurons but also marked by attenuated acetylcholine esterase and choline acetyl transferase activity [100]. Further, SNPs associated with nAChR genes (α3, α4, α7, and β2) have been reported to cause the pathogenesis of AD [101]. Besides, nAChRs are found to trigger synaptopathy due to its up- and downregulation at different sites in AD brain. For instance, chronic Aβ exposure enhanced the levels of α7-nAChR in the hippocampus, cortex, and amygdala both in vivo and in vitro while marked reduction in α4β2-nAChR is observed in the cortical regions of AD patients [102, 103]. Additionally, the interaction between Aβ and α7-nAChR has also been documented in postmortem AD brains [104].

Dopamine (DA)

DA is a major NT in the central nervous system (CNS) and is characterized as an important modulator of synaptic plasticity. Failure of the DA transmission system results in apathy, a negative prognostic indicator of normal aging as well as AD. The occurrences of apathy and motor dysfunctions were predictive of rapid cognitive loss and shorter lifespan in AD patients [105]. Various studies have identified a reduced level of DA at the site of Aβ plaques and NFTs in nigrostriatal regions of AD brain, depicting its prominent role in pathogenesis and impaired cognition [106]. In a study of the 3xTg AD model, Aβ-induced impaired dopaminergic neurotransmission resulted in conversion of LTP into LTD, which led to poor memory and neuroplastic insults in the basolateral amygdaloid nucleus-insular cortex pathway [107]. Moreover, Aβ favored LTD upon low frequency stimulation while restricted LTP after high frequency stimulation. It has also been observed that expression of dopaminergic receptors D1 and D2 is significantly reduced in the prefrontal cortex and hippocampus region of AD patients, while stimulation of dopaminergic transmission improved cognitive function in various animal models of AD. Recently, DA has been shown to possess anti-amyloidogenic and antioxidant effects in mice [108]. Interestingly, the administration of dopaminergic drugs exhibited better cortical plasticity and memory functions in AD patients.

Gamma-amino butyric acid (GABA)

GABA is the principal inhibitory NT in the CNS, which is synthesized by decarboxylation of glutamate with the help of glutamic acid decarboxylase enzyme. Synthesized GABA is transported into vesicles by vesicular GABA transporter at presynaptic terminals of neurons [109]. There are three distinct receptor subfamilies of GABA namely GABA_A, GABA_B, and GABA_C receptors that contribute toward their inhibitory effects, where GABA_A and GABA_C receptors are ligand-gated chloride (Cl^–) channels, while GABA_B receptors are G-protein coupled receptors [110]. The alteration in the balance between inhibitory GABA and excitatory glutamate NTs were found to be one of the pathological factors contributing toward synaptic dysfunction. Aβ fibrils were found to cause perforations in the cell membrane leading to enhanced Ca²⁺ influx mediated over-excitation and consequent epileptic seizures in the hippocampus and cortex. The increased seizures in turn cause alterations in GABAergic sprouting and synaptic inhibition as a protective mechanism to overcome the hyper-excitation of neurons [38]. Immunohistochemical study of GABAergic receptors revealed that α2, β1, and γ1 subunits of GABA_A receptors get upregulated whereas the levels of α1 and γ2 subunits get downregulated in AD brains, indicating a functional remodeling of GABAergic neurotransmission in the cortex of AD patients [111]. Furthermore, elevated inhibitory function of GABAergic synapses induced by glutamate mediated NMDA receptor activation affects the processes required for LTP in dentate gyrus. Therefore, crosstalk between GABA_A receptors and postsynaptic glutamate NMDA receptors are evident in AD pathology [112].

Glutamate

Glutamate is one of the important excitatory NTs that play a crucial role in neural activation with the help of its receptors localized on neuronal membrane. A wide variety of glutamatergic receptors, namely NMDA and AMPA receptors, have been implicated in synaptopathy while normally they are known to regulate synaptic plasticity, neurotransmission, learning, and memory [113]. Numerous studies reported that glutamatergic neurons get lost in response to Aβ accumulation selectively at some synapses in the pathogenesis of AD. These Aβ oligomers also upregulate the extracellular concentration of glutamate in hippocampus of AD brain [39] and directly impact AMPA and NMDA receptors through various subunits including GluR2 and GluN2B. Moreover, Aβ is found to bind with GluR2 subunit via clathrin mediated activation of calcineurin and dynamin [114] and further downregulate AMPA-mediated signal transmission and synaptic plasticity via nuclear translocation of Jacob protein and induction of accompanying CREB shut-off signaling [115]. Furthermore, oligomeric Aβ exposure upregulates GluN2B containing NMDA and extrasynaptic NMDA receptors and disturbs signal transmission [116]. Another study reported an increase in STriatal-Enriched protein tyrosine Phosphatase (STEP) activity upon Aβ and tau exposure leading to GluN2B containing NMDA receptor endocytosis via dephosphorylation of Src kinases Fyn and GluN2B at tyrosine (Y1472) [117]. The increase in STEP activity further disrupts synaptic plasticity and affects cognitive functions in AD. It has also been revealed that Aβ_1 - 42 oligomers form clusters at synaptic junctions and trigger subsequent decreases in the mGlu5 receptor’s mobility and distribution leading to intracellular Ca²⁺ release. The disrupted Ca²⁺ homeostasis triggers mitochondrial dysfunction mediated ATP loss and ROS generation, ultimately causing LTD via GSK3β and calcineurin over-stimulation [5]. Furthermore, Aβ-induced reduction in LTP specifically involves caspase 3 activation and subsequent Akt cleavage in AD patients [118].

Histamine (HA)

HA is a NT that directs crucial physiological functions such as sleep cycle, synaptic plasticity, cognition, and movement. The hypothalamic tuberomammillary nucleus (TMN) is the site in the adult mammalian brain where somas of HA producing neurons are located and extends throughout the CNS [119]. The action of HA is mediated by the activation of four G coupled protein receptors, namely H1R, H2R, H3R, and H4R, which are widespread in the brain. Specifically, H1 receptors were reported to be reduced in the frontal and temporal regions of AD brain. The key association between HA and AD can be ascertained from the fact that the level of HA is markedly elevated in different regions of CNS in AD patients [120]. HA is also found to regulate neuroinflammation along with TNF-α and IL-1β in hippocampal neurons, which is responsible for poor cognition and impaired cerebrovascular functions in AD. Moreover, an association between microglial activation and APOE has been reported in AD patients, where HA levels were found to correlate with APOE; for instance, patients carrying the APOE-4 alleles had lowest HA levels in the brain [121]. Furthermore, it has been identified that HA-containing neurons in the TMN get reduced in association with accumulated NFTs while its level was found to be upregulated in cerebrospinal fluid and serum of AD patients [122].

Norepinephrine

Norepinephrine is a catecholamine, synthesized through a cascade of enzymatic reactions where dopamine is converted into norepinephrine through the action of dopamine β-hydroxylase. Norepinephrine either can act on target receptors (α1, α2, and β) or can be re-uptaken into presynaptic neurons via Na/K-dependent norepinephrine transporters. The primary function of noradrenergic transmission includes regulation of spatial working memory, neuroinflammation, and cellular metabolism [123]. Moreover, norepinephrine also regulates neuroinflammation through adrenergic receptors present in astrocytes and glial cells where any aberration in adrenergic signaling leads to the progression of AD [124]. A recent study evidenced the administration of a selective neurotoxin DSP-4 against noradrenergic neurons that caused enrichment of Aβ deposition, altered spatial memory, and impaired receptor binding sites of α1, α2, and β and upregulation of hyperphosphorylated tau in a transgenic mice model of AD. Furthermore, several studies have also reported impaired LTP and cognition in norepinephrine-compromised hybrid AD mice models [125]. A few reports have linked polymorphisms in the dopamine β-hydroxylase gene leading to reduced norepinephrine production in selective Caucasian populations with AD [126]. In another experiment, the endogenous α2A receptors are shown to contribute in the cascade for AD progression [127]. Likewise, Aβ activates β2 receptors to trigger the hyperphosphorylation of tau via protein kinase-A and c-Jun N-terminal kinase (PKA-JNK) signaling in AβPP/PS1 mice model [128].

Serotonin

Serotonin is a biogenic monoamine, which regulates important physiological functions in CNS such as mood, pain, anger, aggression, sleep, and appetite [129], and it serves as both NT as well as NM [130]. In general, serotonin regulates crucial mechanisms like learning and memory both in healthy as well as in aged individuals. This is the reason that neurological disorders such as AD are marked by aberrant serotonergic signaling and altered 5-hydroxytryptamine (5-HT) metabolism in the CNS [131]. A specific class of receptors called the 5-HT receptors orchestrates the activity of serotonin. Though a number of 5HTRs (5HT2AR, 5HT2CR, 5HT4R etc.) are involved in AβPP processing, 5HT4R has gained attention by reinstating a neuroprotective environment by inducing non-amyloidogenic AβPP cleavage mediated release of soluble AβPPα [132, 133]. The investigations reported reduced levels of serotonergic neurons and 5HT metabolites in the raphe nuclei of AD postmortem brains [134, 135]. Likewise, Aβ plaques in the projection site of serotonergic neurons triggered 5HT neuronal apoptosis accompanied by loss of neuronal cell bodies in an AβPP transgenic mice model [136]. Additionally, a link between tau phosphorylation and 5HTRs have further strengthened the notion that 5HTRs are closely associated with AD via Fyn mediated ERK1/2 activation [137]. Moreover, tau hyperphosphorylation in the raphe nuclei is also evident to induce 5HT-mediated neuronal cell death in AD brain [138]. The altered NTs/NMs and their associated factors in the etiology of AD have been depicted in Fig. 2.

Fig.2

Molecular mechanisms associated with defective neurotransmitters/neuromodulators (NTs/NMs) in Alzheimer’s disease and their associated factors. GABA, γ-Aminobutyric acid; L-DOPA, L-3,4-dihydroxyphenylalanine P₂X₇, purinoceptor 7, P₂Y, purinoceptor;DSP-4, neurotoxin; NMDAR, N-methyl-D-aspartate receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; H₃R, histamine receptor, nAChR, nicotinic acetylcholine receptor; 5HTR, 5-hydroxytryptamine (serotonin receptor); D₂R, dopamine receptor D2; AβPP, amyloid-β protein precursor; ATP, adenosine triphosphate; ADP, adenosine diphosphate; ROS, reactive oxygen species; VLDLR, very-low-density-lipoprotein receptor; TRP, transient receptor potential.

OTHER NEUROTRANSMITTERS/NEUROMODULATORS

Additionally, various other NTs/NMs such as Reelin, Interleukin-33 (IL-33), Purinergic receptors, and TRP channels are identified that contribute significantly in the synaptopathy of AD. For instance, disruption in the activity of Reelin causes aberrant hyperphosphorylation of tau by altering the signaling cascades associated with GSK3β activity [139]. Another NT, interleukin-33 (IL-33), is found to regulate inflammation in neuronal cell since IL-33 depletion released IL-1β and TNF-α that contributed well in neuroinflammatory synaptic loss in AD brain [140]. Likewise, dysfunction of purinergic receptors also causes neuroinflammation, ATP release, and alteration in Ca²⁺ influx and thus induces LTD at synaptic junctions [141]. There are several TRP channels (TRPC, TRPV, TRPM, TRPP, TRPML, and TRPA) that are involved in the alteration of Ca²⁺ influx, modulation of the PSD95 pathway, and GSK3β phosphorylation mediated synaptic plasticity [142, 143]. Herein, the potential mechanisms of synaptopathy associated with NTs/NMs have been described in (Table 3).

Table 3

List of neurotransmitters/neuromodulators and their mechanism associated with synaptopathy in AD

Neurotransmitters/ Neuromodulators	Involved causative factors/receptors	Involved mechanisms in synaptopathy	Principle phenotype	References
Acetylcholine (ACh)	Aβ, tau, cholesterol depletion, metal ion dyshomeostasis, and oxidative stress	Abnormalities in AChR causes downregulation of both MAPK-CREB and PI3K-Akt signaling cascade and also causes alteration in the level of glutamate that affects synaptic plasticity		[144, 145]
Glutamate	Factors associated with inhibition of protein phosphatases, Aβ, tau, cholesterol depletion, metal ion dyshomeostasis, IGF-1 depletion, altered level of dopamine, and elevated level of glucose	Glutamate toxicity causes alteration in the level of intracellular Na⁺, K⁺, and Ca²⁺. It also causes impairment in NMDA, AMPA, and mGlu receptor and ultimately impairs LTP and LTD thus induces synaptic loss associated cognitive decline		[39 , 146–149]
Gamma Amino Butyric Acid (GABA)	KNCQ Channels, AβPP, Aβ, mitochondrial dysfunction, lipid depletion, and altered level of dopamine	GABAergic dysfunction causes alteration in Ca²⁺ channels and block μ-opioid receptors thus impairs synaptic plasticity		[38 , 150–153]
Noradrenaline/ Norepinephrine	Microglia dysfunction, involvement of complement system, usage of DSP-4 and reserpine, and knockout of DβH enzyme	Norepinephrine dysfunction causes alteration in PKA-JNK pathway, microglia activation, and impairs LTP and LTD, thereby leading to synaptic loss associated with cognitive decline		[123 , 155]
Serotonin	Aβ and tau	Dysfunction of serotonin impairs cholinergic receptors, diminishes arachidonic acid (AA) uptake and causes axonal dysfunction thereby leading to the degeneration of raphe monoamine neurons and triggers synaptic loss associated with memory loss	Alzheimer’s Disease	[138 , 157]
Histamine (HA)	Impact of GABAergic and glutamatergic receptors and dysregulation of mast cells	HA dysfunction impairs cholinergic and NMDA receptors, leading to synaptic dysfunction		[158]
Reelin	APOER2, VLDLR, DAB1 dysfunction, and Aβ	Depletion of Reelin causes alteration of signaling pathways that regulates GSK3β activity and enhances the level of hyperphosphorylated tau thereby leading to dysfunction of synapses		[159 –161]
Purinoceptors	Loss of P2X₇ and P2Y₂, microglia activation, and Aβ	Loss of P2X₇ and P2Y₂ receptors causes neuroinflammation via activation of microglia and dysfunction of Rac1 protein which thereafter causes dysregulation of Aβ phagocytosis that ultimately leads to synaptic loss		[162 –164]
Interleukin-33 (IL-33)	Microglia activation, Aβ, increased level of IL-1β and TNF-α	IL-33 is proinflammatory in CNS and activates inflammatory cells thereby leading to the disruption of synapses		[140, 165]
TRP Channels	Factors associated with oxidative stress and mitochondrial dysfunction, Aβ, mutated PSEN1 and AβPP	TRP channels disrupt Ca²⁺ homeostasis and alters various signaling cascade leading to synaptic loss		[166]
Dopamine (DA)	Aβ, Ca²⁺, degeneration of cholinergic neurons, and inactivation of p38-MAPK pathways	DA dysfunction causes alteration in glutamatergic and cholinergic transmission, impairs physiological cell metabolism, activates various enzymatic pathways, leading to apoptosis and synaptic loss		[106, 167]

CORRECTION MECHANISMS TO TARGET PERTURBED NEUROTRANSMITTERS/NEUROMODULATORS IN SYNAPTOPATHY

Presently, treatment against defective NT/NM-mediated synaptopathy in AD has become a demanding task for neurobiologists since there is not a single factor responsible for such abnormalities but a massive numbers of factors associated with widely dispersed signaling cascades. Nevertheless, defective NT release at the synaptic junction causes several detrimental effects, which are associated with the altered activity of synaptic proteins, transcription factors, Ca²⁺ homeostasis, and other molecules critical for neuronal plasticity [168]. These detrimental effects further disrupt the neuronal homeostasis and thereby cause the synaptic insults. In order to overcome such complications, numerous therapeutic strategies are currently being devised that alleviate the toxicity associated with defective NTs/NMs. For instance, numerous biological compound-based therapies have been designed to overcome the problems associated with these defective NTs/NMs in AD. Moreover, current therapeutic approaches have also been discussed here that can slow down the pathophysiology behind defective NT/NM-mediated synaptic dysfunction.

Biological compound-mediated therapy for altered neurotransmitters/neuromodulators in synaptopathy

The reduction in cholinergic neurotransmission in AD has led to the development of numerous compounds as the first-line of treatment for the pathological phenomenon of this disease. The clinical advantages of these compounds include significant improvements in NT release, improvement in altered synaptic plasticity, and attenuation of memory loss and cognitive failure. Several compounds have been identified so far to target altered NT/NM activity in AD. Curcumin, a major active component of turmeric, has been found to regulate the levels of dopamine, norepinephrine, serotonin, and glutamate in the brain and thus significantly reduce behavioral symptoms of AD. Moreover, it also acts as an inhibitor of mono-amine oxidase (MAO)-A and MAO-B enzyme, which is also crucial for depleting dopamine and serotonin [169]. Similarly, galantamine, an acetylcholinesterase inhibitor and an allosteric regulator of nAChR, has been reported in the treatment of severe dementia associated with AD. Additionally, it also influences diverse other NT systems, possibly modulating the activity of dopamine, serotonin, glutamate, and GABA in certain nerve tracts [170]. Further, numerous other chemical compounds, including donepezil (E2020), rivastigmine, and tacrine have been introduced for the inhibition of acetylcholinesterase activity in AD [171]. Currently, nicotine has also been reported to reduce Aβ toxicity through the activation of α7 nicotinic acetylcholine receptor/phosphatidylinositol 3-kinase (α7nAChR/PI3K) signaling pathway and its cross-talk with the Wnt signaling pathway [172]. In a study, the effects of natural cannabinoids (Sativex^®) have been reported to improve dopamine neurotransmission [173]. Similarly, many other biological compounds have been identified and implicated so far to target altered NT activity in the AD brain, which have been outlined in Table 4. These compounds bind to NTs and their specific receptors thereby reducing the severity of diseaseatmosphere.

Table 4

List of potent biological compounds involved in alleviating the neurotoxic effect of altered neurotransmitters/neuromodulators in synaptopathy

SN	Biological compounds	Associated protective mechanisms against synaptic loss	Principle phenotype	References
1	Anthocyanine (ANT)	It regulates ion pump activity and cholinergic neurotransmission. Further, it also enhances memory and act as an anxiolytic compound		[174]
2	Oridonin (Ori)	Augments the expression of PSD-95 and synaptophysin and also promotes mitochondrial dynamics in the synaptosomes of AD mice thereby leading to attenuate synaptic loss and cognitive deficits. Moreover, it also activates the BDNF/TrkB/CREB signaling pathway in the hippocampus of AD mice		[175]
3	Asiaticoside	It prevents spatial learning and memory decline by scavenging free radicals, decreasing the level of Aβ, upregulating the activity of antioxidant enzymes, ameliorating dysfunction in synaptic plasticity and reversing abnormal changes in ACh level and AChE activity		[176]
4	Cotinine	The beneficial effects of cotinine are accompanied by an increase in the expression of the active form of PKB and the PSD-95 in the hippocampi and frontal cortices of Tg6799 mice. This PSD95 plays a crucial role in promoting brain plasticity by modulating NMDA receptor signaling. Additionally, it also increases 5-HT levels in the rat brains thereby stimulating the serotonergic activity in AD brain		[177]
5	Piracetam	It is a derivative of the neurotransmitter GABA and modulates neurotransmission in a range of transmitter systems (including cholinergic and glutamatergic), thus improves neuroplasticity. It also significantly restores impaired synaptic function by attenuating numerous mitochondrial dysfunctions such as, mitochondrial membrane potential and ATP production, induced by Aβ in PC12 cells		[178]
6	Naringin	It improves long-term learning and memory ability by both enhancing the autophosphorylation of CaMKII and increasing the phosphorylation of the AMPA receptor at a CaMKII-dependent site	Alzheimer’s disease	[179]
7	7, 8-dihydroxyflavone (7,8-DHF)	Inhibits the loss of hippocampal synapses, restores synapse number and synaptic plasticity, and prevents memory deficits induced by impaired BDNF/TrkB signaling pathway in the hippocampus of AD mice		[180]
8	Memantine	A non-competitive NMDA receptor antagonist attenuates cognitive impairment and synaptic dysfunction by restoring protein phosphatase-2A activity via decreasing its demethylation at Leu309 selectively in adeno-associated virus vector-1-I1PP2A rats. Further, it also alleviates glutamate mediated cell excitotoxicity by excessive stimulation of NMDA receptors in astrocytes and neurons		[181]
9	Propofol	Acts as a GABA_A receptor agonist which reduces Aβ generation and accelerates Aβ degradation. Further, it ameliorates cognitive function and attenuates caspase-3, caspase-9 activation in AD mice model		[112]
10	Metformin	It alleviates the increase of total tau, phospho-tau and activated JNK. Further, it also attenuates the reduction of synaptophysin, a synaptic protein in the db/db mouse hippocampus		[182]
11	Cannabidiol (CBD)	It shows neuroprotection by normalizing the caspase 3 activity, the main integral transmembrane protein of synaptic vesicles (synaptophysin) and mitochondrial fission protein DNM1L expression levels in rats with brain iron overload. CBD treatment has also been reported to improve dopamine neurotransmission in in a mouse model of tauopathy		[79, 183]
12	Dizocilpine (MK801)	MK801 alleviates glutamate mediated cell excitotoxicity by excessive stimulation of NMDA receptors in astrocytes and neurons		[184]
13	UBP141	UBP141, an astroglial NMDA receptors antagonist plays a potential therapeutic role against synapses loss		[185]
14	Levetiracetam	Chronic levetiracetam administration reduces glutamate excitotoxicity and enhances the levels of inhibitory neurotransmission thereby attenuating cognitive abnormalities in AD		[186]
15	Muscimol	Selective GABA_A receptor agonist provides protection against Aβ-induced neurotoxicity in hippocampal, retinal and cortical neurons in rodents		[187]
16	Etazolate (EHT-0202)	The GABA_A receptor modulator protects neurons against Aβ-induced toxicity thereby displaying anti-inflammation effect after traumatic brain injury and improves cognition in mice models		[188]
17	Pentobarbital	Stimulation of GABA receptors by pentobarbital restores neuronal maturation and neurogenesis in apolipoprotein E4 (APOE4) knocking mice. APOE4 is known as a genetic risk factor for early onset AD perhaps by accelerating Aβ plaque formation, or by impairing neuron repair		[112]
18	Flumazenil or picrotoxin	Chronic systemic treatment with GABA_A antagonists restores memory loss in AD		[189]
19	EVP-6124	EVP-6124, a selective agonist of the α7 nAChR, exerts an excitatory effect on the postsynaptic neuron thereby leading to LTP and memory formation		[190]
20	D-serine acid oxidase	Treatment with D-serine acid oxidase attenuates NMDA-induced excitotoxicity		[191]
21	5,7-dicholorokynurenic acid	The physiological glycine site antagonist kynurenic acid protects against NMDA-induced excitotoxicity		[191]
22	Methyl-4- carboxyphenylglycine (MCPG)	MCPG, a non-selective group I/II mGluR antagonist, prevents the reduction induced by Aβ in miniature excitatory post-synaptic cells		[192]
23	2-methyl-6-(phenylethynyl)- pyridine	An mGluR5 antagonist rescues LTP facilitation in murine hippocampal slices induced by oligomers of Aβ extracted from AD brains		[192]
24	SIB1757	An mGluR5 antagonist prevents LTD facilitation in rat hippocampal slices induced by oligomers of Aβ extracted from AD brains		[193]
25	Melatonin	It shows neuroprotection against Aβ induced neurotoxicity, mediated by activation of GABA receptors and the resulting hyper-polarization of the neurons		[194]
26	6,7-dinitroquinoxaline-2,3-dione	An AMPA receptor and kainate receptor antagonist attenuates excitotoxic cell death induced by Aβ retinal cell cultures		[192]

Recent therapeutic strategies for targeting perturbed neurotransmitters/neuromodulators in synaptopathy

Although the significant role of distinct chemical compounds has been explored extensively to target altered NTs/NMs in synaptopathy, there are numerous other new therapeutic strategies that have been identified so far to target such alterations. For instance, the neuroprotective effect of Nanodiamond against memory deficits has currently been reported, where it showed a protective role by modulating NF-kB and STAT3 signaling cascade, the effects mediated by the regulation of NMDARs [195]. Further, treatment using vitamin D3 has shown a protective role against synaptic loss via significantly increasing the levels of ACh in neurons [196]. Treatment with zinc ion (Zn²⁺) showed enhanced levels of NT release in aluminum (Al³⁺)-treated animals, thereby showing their protective role against synaptic injury, since Al³⁺ exposure decreases the level of NTs and acetylcholinesterase activity in brain and leads to the neuronal dysfunction [197]. Similarly, elevated levels of magnesium ion (Mg²⁺) also exert substantial synaptoprotective effects in AD brains where it controls the synaptic density/plasticity bt preventing the onset of impaired NMDA receptor signaling pathway [198]. Interestingly, insulin is being implicated nowadays to attenuate the cognitive dysfunctions through its regulatory effect on the expression of NMDA receptors and on the associated insulin signaling cascade in AD [199]. Another therapeutics strategy to ameliorate Aβ-mediated synaptic loss is using Substance P, which is a member of the tachykinin family, distributed widely in the CNS and acts as a NT/NM as well as neurotrophic factor. Further, Substance P is able to provoke non-amyloidogenic AβPP processing, thereby curtailing the feasibility of Aβ peptides production in the brain [200]. Additionally, several studies have highlighted the role of the ubiquitin-proteasome system as a therapeutic approach to target synaptic loss induced by altered release of NTs at synapses. The ubiquitin-proteasome system is found to modulate NTs/NMs, synaptic proteins, transcription factors, and other molecules critical for neuronal plasticity. For instance, altered NMDA receptors are retro-translocated and degraded by a F-box protein called Fbx2, advocating that SCF-type ligases targets NMDA receptors for ubiquitination [201]. Another protein Nedd4-1, known as a HECT E3 ubiquitin ligase, has also found to target Aβ-induced reductions in surface AMPARs, dendritic spine density, and synaptic strength [202]. Likewise, heat shock protein (HSP)-based therapeutic approach has also been currently addressed in numerous studies. For example, HSP90 is being used nowadays to modulate NT release at the presynaptic terminals independently by mediating the continuous cycling of synaptic AMPA receptors [203]. Moreover, the hypothetical representation of numerous pharmacological approaches to compensate neurotransmission imbalance has been depicted in Fig. 3. Nevertheless, several other suitable approaches still need to be devised in the near future for effective treatment against synaptic dysfunctions mediated by altered NTs/NMs.

Fig.3

Pictorial representation showing the involvement of different therapeutic approaches against synaptic loss associated with impaired neurotransmitters/neuromodulators (NTs/NMs). Fbx2, F-Box Protein 2; IGF-1, insulin-like growth factor 1; brain-derived neurotrophic factor; NF-kB, Nuclear factor-κB; STAT3, signal transducer and activator of transcription 3; Hsp90, heat shock protein 90; Hsp27, heat shock protein 27.

CONCLUSION

In this review, we have discussed the pertinent role of synaptic plasticity in memory formation, its stabilization, and associated abnormalities due to Aβ accumulation and tau phosphorylation. For instance, increased levels of toxic Aβ and tau oligomers at synaptic junctions are responsible for neuronal toxicity, which is associated with synaptic loss in AD. Similarly, involvement of oxidative stress, activation of redox signaling, and subsequent damage to mitochondrial integrity in synaptic alteration has also been elucidated. Additionally, the altered activity of various NTs/NMs including glutamatergic, GABAergic, and acetylcholinergic receptors with respect to Aβ accumulation and tau phosphorylation has also been extensively reviewed, since NTs/NMs in their normal form play a crucial role in maintaining neuronal homeostasis in the brain. However, any alterations in their proper functioning cause several neurotoxic effects associated with altered activity of synaptic proteins, transcription factors, Ca²⁺ homeostasis, and other molecules critical for neuronal plasticity. These factors under the diseased state disrupt normal homeostasis of neurons, thereby causing synaptic loss. Furthermore, in order to target the malfunctioning NTs/NMs or reverse their associated chronic effects, numerous biological compound-mediated therapeutic strategies have been discussed to obviate the disease symptoms of AD. Additionally, recent therapeutic strategies for targeting synaptic loss induced by defective NTs/NMs have been addressed. Finally, this review accentuates the savvy of altered redox signaling and impaired neurotransmission in synaptic dysfunction during synaptopathy that could unveil mechanism-based therapeutics and ameliorated inferential strategies.

Footnotes

ACKNOWLEDGMENTS

The authors would like to thank the DTU senior management for encouragement and facility.

Authors’ disclosures available online ().

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