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1. Introduction

Alzheimer’s disease (AD) is the most common and prevalent neurodegenerative disease with memory dysfunction and cognitive impairment, affecting nearly 46.8 million people worldwide, as reported by the World Health Organisation. AD is characterized by extracellular deposition of amyloid-β (Aβ) senile plaques and intracellular accumulation of neurofibrillary tangles (NFTs) [1]. Aβ is a short peptide that is produced from amyloid precursor protein (APP), a type I integral membrane glycoprotein which undergoes cleavage by both amyloidogenic and non-amyloidogenic pathways [2]. Amyloidogenic pathway produces soluble APPβ (sAPPβ) fragment, Aβ, and APP intracellular domain (AICD) through sequential cleavage of APP by β-secretase and γ-secretase; non-amyloidogenic pathway generates soluble APPα (sAPPα), P3 peptide and AICD by α-secretase and γ-secretase [3]. Out of all Aβ species, soluble oligomeric Aβ1-42 is considered as the most neurotoxic product obtained after cleavage of APP [4]. Aβ was first identified in the extracellular component and later studies confirmed its presence in neuronal intracellular regions such as the endosome [5], endoplasmic reticulum [6], and trans-Golgi network [7]. Aβ in mitochondria reacts with proteins impairing oxidative phosphorylation and increasing reactive oxygen species (ROS) that damage the neuronal membrane ^[8][9][10][8,9,10].

Aβ peptides are involved in cognitive dysfunction by inducing synaptotoxicity through Aβ aggregation. Aβ species can be found at the synapse as low-molecular-weight (LMW) dimers, trimers, and tetramers) and high-molecular-weight (HMW) oligomers [11]. HMW Aβ oligomers have greater binding affinity in hippocampal neuronal synapses when compared to LMW Aβ oligomers [12]. However, LMW Aβ oligomers induce more cognitive dysfunction and HMW Aβ oligomers cause a transient decrease in cognitive functions [13]. Nevertheless, HMW oligomers can dissociate into LMW species impairing synaptic functions [14] and in contrast, dissociation of Aβ oligomers into monomers in vivo could reduce Aβ pathology and synaptotoxicity [15]. Aβ oligomers target the excitatory synapses with greater affinity and alter the structure and functions of the synapses [16].

Tau is a microtubule-associated protein (MAP) engaged in the stability of microtubules in neurons and also regulates synaptic function [17]. Hyperphosphorylation of tau results in the formation of NFTs, which is a major pathological hallmark of AD. Tau phosphorylation acts as an indicator of aberrant activities of kinases and phosphatases in AD [18]. In dendrites, hyperphosphorylation of tau forms fibrils, which appear as neuropil threads and as NFTs in axon and the somatodendritic section of neurons ^[19][20][19,20]. Tau protein undergoes phosphorylation by proline-directed protein kinases (PDPKs) or non-proline-directed protein kinases (non-PDPKs) [21]. PDPKs include Cyclin-Dependent Kinase-5 (Cdk-5), Glycogen synthase kinase-3 (GSK-3), and extracellular signal-related protein kinase (ERK). The irregular activity of Cdk-5 in AD causes tau hyperphosphorylation, loss of dendritic spines, and deterioration of synaptic plasticity [22]. Non-PDPKs comprise of protein kinase A (PKA), Casein kinase 1 (CK1), and Casein kinase 2 (CK2) [18]. Among the kinases identified to be responsible for tau hyperphosphorylation, GSK-3β plays an important role in the pathological changes of tau protein in AD [23]. Data collected in humans show increased activation of GSK-3β in early-stage AD [24], while a consistent inhibition was observed in late-stage AD ^[25][26][25,26], thus suggesting that GSK-3β-mediated tau phosphorylation is among the earliest events during the progression of the pathology. Increasing evidence shows that tau in dendrites plays a key role in Aβ-induced detrimental effects. Of note, tau knockout mice showed a decrease in extrasynaptic N-methyl-d-aspartate (NMDA) receptor activity in the hippocampus contributing to neuroprotective effects [27]. Accumulation of Aβ plaques in synapse and the infiltration of tau into dendritic spines reduce excitatory glutamatergic synaptic transmission leading to cognitive impairments [28].

In the central nervous system (CNS), glutamate is the primary excitatory neurotransmitter acting on both ionotropic and metabotropic receptors. It is at the crossroad between multiple metabolic pathways and plays an important role in the functions of learning and memory. The activity of glutamatergic neurons is compromised in AD due to the destruction of synapse and neuronal death and its deficit can influence memory, cognition, and behavior, including cortical and hippocampal processing ^[29][30][29,30]. On the other hand, the pathological accumulation of glutamate can induce neurotoxicity due to time-related exposure, over-stimulating the post-synaptic response causing an increase in the entry of Ca²⁺  into neurons [31]. Since currently available therapies of AD include cholinesterase inhibitors, NMDA partial antagonist memantine, more information about AD-related changes in glutamate neurotransmission would be highly relevant to better understand its mechanisms of action and to optimize the treatment ^[32][33][32,33]. In fact, treatment using memantine has improved cognition, behavior, global function but the degree of efficacy remains to be fully determined.

2. Glucose Levels Affect Glutamate Content in AD

AD patients commonly suffer from other co-morbidities (stress, depression, diabetes, renal disease, etc.) that increase the complexity of AD pathogenesis ^{[34][35][36][37][38][39][40]}[34,35,36,37,38,39,40]. Among all the co-morbidities, diabetes remains the most prevailing and significant risk in developing AD ^{[41][42][43][44][45][46]}[41,42,43,44,45,46]. Familial AD patients exhibit alterations in the cerebral glucose metabolism before the manifestation of amyloid plaques that might be the causative reason for AD development ^[47][48][47,48].

Glucose is the main energy substrate for the brain cells (glial cells and neurons). It is now well established that aberrations in cerebral glucose utilization, glycolysis, and oxidative metabolism are associated with cognitive dysfunction in AD ^{[43][48][49][50][51]}[43,48,49,50,51]. There is a particular pattern of regional brain glucose hypometabolism in AD affecting the parietal and temporal cortices, where the glucose deficit is on the order of 20–25% compared to age-matched, cognitively normal controls [52]. Many studies indicate that presymptomatic brain glucose hypometabolism can be present long before the threshold of cognitive symptoms of AD and could therefore potentially be contributing to the development and/or progression of both the cognitive decline and the neuropathological hallmarks associated with AD. To this regard, although a neuropathological link has not yet been fully demonstrated in humans, increasing evidence in transgenic mouse models of AD suggests that various experimental approaches to diminishing brain glucose supply all drive Aβ overproduction [53]. Moreover, both type-2 diabetes and its associated brain insulin resistance were proposed to favour tau hyper-phosphorylation in AD, although the molecular mechanisms are still unclear ^[51][54][55][51,54,55].

During the course of time, glucose alterations in the brain have a detrimental effect on the glutamatergic system due to an imbalance in glutamate availability. Neurons and glial cells work in tight cooperation in the glutamate/glutamine cycle and this cycle is connected with the energy metabolism, and, in turn, with the availability of glucose to the brain. Glutamate can be converted into α-ketoglutarate and vice-versa and serves as a substrate in the tricarboxylic acid (TCA) cycle. Research on APPswe/PSEN1dE9 mice showed that prior to amyloid plaque deposition, brain energy metabolism is affected leading to changes in glucose metabolism, reduced TCA cycle activity, decreased adenosine triphosphate (ATP) synthesis in isolated mitochondria were observed demonstrating that alterations in cerebral energy metabolism precede the amyloid plaques formation [56]. The conversion of glutamate to glutamine by the enzyme glutamine synthetase requires ATP and it has been estimated that 70% of the signaling energy comes from the oxidation of glucose [57]. Therefore, impairment in glucose metabolism impacts the glutamate receptor-mediated signal pathway leading to initial stages of memory impairment observed in patients affected by AD ^[58][59][58,59]. Figure 1 describes how alterations in cerebral glucose levels affect glutamate output leading to neuronal death in AD.

Figure 1. Presynaptic terminals release glutamate activating ionotropic receptors on postsynaptic neurons. In normal conditions, N-methyl-d-aspartate (NMDA) NR2A activation induces an increase in calcium levels favoring the induction of long-term potentiation (LTP) through metabolic pathways (extracellular signal-related protein kinase (ERK), CaMK II, cyclic adenosine monophosphate response element-binding protein (CREB)). Excess glutamate left is taken up by astrocytes through EAAT2 converting into glutamine and glutamate by glutamine synthetase and glutaminase respectively (black arrows). The synthesized glutamate is transported into vesicles by VGlut1/2. Conversely in Alzheimer’s disease (AD), Aβ oligomers interfere with NMDA receptors increasing the spillover of glutamate (red arrows) to extrasynaptic sites activating NMDA NR2B receptors increasing excess calcium levels inhibiting prosurvival pathways. Imbalance in the glutamate/glutamine cycle (black-dashed arrows) is also reported in the figure.

3. Therapeutics for AD

Drug discovery, research, and development for AD are strenuous and challenging. Over hundreds of drugs have failed and, currently, there are 132 agents in clinical trials for AD treatment. Since 2003, no new drugs and no disease-modifying treatments (DMTs) have been approved for AD ^[60][209]. Current treatment of AD includes drugs targeting the cholinergic system such as donepezil, rivastigmine, galantamine; drug acting on the glutamatergic system like memantine, and drugs that intervene both cholinergic and glutamatergic system namely Namzaric, a combination of memantine and donepezil ^[61][210]. Compounds acting on glutamatergic receptors, transporters, and their key findings are listed in table 1.