INTRODUCTION:

In the United States, more than five million people have Alzheimer's disease (AD), with people 65 and older making up the bulk of those affected¹. By 2026, there will be fourteen million Americans living with Alzheimer's disease, according to the Alzheimer's Association Report. The condition, which is the most common type of dementia, is a progressive and irreversible brain disorder that slowly erodes a person's cognitive abilities. It progresses from early-stage, early-stage, moderate-stage, and late-stage disease².

Memory loss and cognitive impairment are the main early signs. Cognitive function deteriorates as the disease advances to its latter stages, and physical limitations like the inability to walk, sit, or eat are a sign of this³. Intracellular neurofibrillary tangles and extracellular amyloid plaques are the defining signs of AD that have been found in the cortical and limbic regions of the brain⁴. Over the past few decades, multi-target therapies have been under more and more consideration as alternate approaches to managing multifactorial AD. Combination therapy based on the "cocktail medication-multiple targets" strategy, which combines many pharmaceuticals working independently on distinct targets, have been used to treat AD symptoms, including mild to moderate AD⁵. One such drug combination is memantine and donepezil. These medications may influence the targets of several or related processes implicated in the pathophysiology of AD⁶. However, they are frequently accompanied by adverse effects brought on by pharmacological interactions, such as bradycardia, atrioventricular block, and psychosis, in addition to the different pharmacokinetic profiles of each component drug⁷.

METHODS:

Materials:

Another multi-target method that takes the "one compound-multiple targets" tack has surfaced and is thought of as a polypharmacological therapy for AD. A single pharmacological molecule is created in such a method to concurrently target two or more distinct proteins implicated in the onset of AD. In contrast to several medications delivered in combination, a single ligand can advantageously avoid side effects from interactions among drugs in combination therapy with a more predictable pharmacokinetic profile⁸. Additionally, it can improve a patient's adherence to straightforward dose schedules. In order to control the development of a disease, multi-target medications may thus constitute a potential therapeutic option to combination therapy. The pathophysiology of AD and the current pharmacological therapy are covered in the sections that follow. In addition, elaborated multi-target therapy for the illness based on polypharmacological ligands⁹.

The NMDA receptor may possibly play a role in the etiology of AD. Long-term potentiation (LTP) is a process that, in essence, enables regulation of synaptic plasticity and offers typical learning and memory capabilities through binding of the glutamate excitatory neurotransmitter to the NMDA receptors¹⁰. According to an excitotoxicity theory for AD, the A plaques overactivated the NMDA receptors, which increases Ca²⁺ fluxes excessively, causing excitotoxicity and impairing mitochondrial energy metabolism. As a result, free ROS generation is encouraged, which raises oxidative stress and changes synapse function¹¹. In addition, A oligomers caused spine loss, which decreased the number of glutamate receptors available for binding and inhibited LTP at the hippocampus and other brain areas. It encourages further development of AD without appropriate excitatory transmission through NMDA receptors and normal synaptic function. Since AD causes cognitive impairment, the NMDA receptors have been suggested as prospective therapeutic targets¹².

A cholinergic theory has also been proposed for the pathophysiology of end-stage Alzheimer's disease. According to the concept, Alzheimer's disease is caused by the death of central cholinergic neurons, which results in a lack of acetylcholine, a neurotransmitter involved in memory and learning (ACh)¹³. According to research, the AD brain has significantly reduced activity of choline acetyltransferase (ChAT), which is involved in acetylcholine production, as well as impaired metabolism of acetylcholinesterase (AChE)¹⁴. Nonetheless, cholinergic depletion is not the main cause of cognitive function reduction.Aging, on the other hand, causes natural loss of ACh and reduces the ability of cholinergic neurons to release ACh for neurotransmission; this makes the hippocampus more vulnerable to injury from other central nervous system issues, such as stress, seizure, or stroke¹⁵. Finally, this has resulted in memory and cognitive problems in AD. Aside from cholinergic routes, AChE has been linked to non-cholinergic function via AChE-induced A aggregation, which can eventually lead to neurotoxicity¹⁵.

Most therapeutic medications on the market are single-target treatments suggested for a variety of disorders¹⁶. However, single-target medications have been proven to be increasingly ineffective against disorders with multifactorial pathophysiology, such as Alzheimer's disease¹⁶. Indeed, as indicated in the preceding section, single-target FDA-approved medications are the most prevalent therapy alternatives for AD; nevertheless, these drugs are only useful in treating symptoms of AD, not in preventing disease progression¹⁷. Drugs that target numerous pathogenic pathways or targets have been proposed as another possibility for managing the course of Alzheimer's disease. Although combination therapy including two single-target medications is now utilized to treat Alzheimer's disease, such a therapy may result in an increased incidence of undesirable effects and a decrease in efficacy¹⁸.

Based on these targets, libraries of compounds can be biologically screened to find hits with polypharmacological activities¹⁹. These hits, like molecules developed from knowledge-based/medicinal chemistry-based techniques, can be structurally changed to optimize the overall profile. Understanding the function of different targets in AD development, in tandem with knowledge of pharmacophores with related biological activities, would undoubtedly aid in the design of multi-target ligands against important targets of interest^19-22. To create novel multi-targeted ligands for Alzheimer's disease, the medicinal chemistry-based strategy employs the chemical structures of compounds with documented anti-Alzheimer properties as well as those of approved medications. These hybrid compounds are created rationally by combining numerous known pharmacophoresinto a single pharmacological entity. In addition to structural optimization for maximum activity, physicochemical and pharmacokinetic aspects are considered in the development of hybrid drugs. This section illustrates several examples of these molecules classified as conjugate, merged, and fused hybrids^23-29.

Therapeutic targets of AD and their role in AD pathogenesis^30-38

Therapeutic Target	Role in AD Pathogenesis
AChE	To hydrolyze ACh in synapses To form complexes with Aβ peptide, modify its conformation and promote itsaggregation to form β-amyloid plaques
BuChE	To hydrolyzeACh and the concentration of BuChE is found to be increased in advanced AD
BACE-1	To work with γ-secretase to degrade APP and generate Aβ peptide
GSK-3β	To hyperphosphorylate Tau proteins, separate them from microtubules and aggregate them into insoluble NFTs To regulate γ-secretase to induce Aβ peptide formation
MAO: MAO-A and MAO-B	To catalyze oxidative deamination To increase production of hydrogen peroxide and ROS To cause oxidative injuries and a toxic environment of neurodegeneration
Metal ions	Excess metals in brain cause peptide aggregation and oxidative stress Dysregulation of Cu2+ and Zn2+ induces generation of toxic Aβ oligomers by binding to Aβ peptides
NMDA receptor	To modify major forms of synaptic plasticity that contribute to learning and memory, and to consolidate short-term memory into long term memory Its overstimulation by excess glutamate will cause excitotoxicity and cell death Appropriate inhibition will improve the condition of AD patients
5-HT receptor (serotonergic receptor)	5-HT1A receptor has a therapeutic role in depressive disorder; the agonist and antagonist could be potential therapies for AD 5-HT4 receptor partial agonist can enhance ACh release, promote non-amyloidogenic cleavage of APP, form neurotrophic human sAPP-α fragments and decrease Aβ secretion 5-HT6 receptor antagonist can alleviate AD symptoms by enhancing cholinergic neurotransmission
SERT	To transport serotonin from the synaptic cleft back to the presynaptic neuron To terminate serotonergic signaling through reuptake of neurotransmitters into presynaptic neuron
PDE	To hydrolyze and degrade secondary messengers including cAMP and cGMP Regulators of signal transduction in neuroplasticity and neuroprotection Its inhibition can decrease the GSK-3β activity and level of hyperphosphorylated tau proteins
CB2 receptor	Activation of CB2 receptor reduces production of pro-inflammatory molecules by modulating migration of macrophages
H3 receptor	Activation of H3 receptor (autoreceptor and heteroreceptor) provides negative feedback in the histaminergic system Its activation also inhibits release of other neurotransmitters
AGEs	Glycation of tau proteins, leading to formation of paired helical filaments Glycation of Aβ peptide, resulting in increase in self-aggregation To provoke generation of reactive oxygen species
FAHH	To degrade endocannabinoid mediator, anandamide; endocannabinoid system in CNS plays a crucial role in learning and memory Its expression is elevated during inflammation and neurodegenerative processes
Nrf2	One of the components in Kelch-like ECH-associated protein 1 (Keap1)- nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway involved in defense mechanisms of cells against oxidative stress To initiate transcription of antioxidant genes and phase II detoxifying genes Its activation inhibits the induction of pro-inflammatory cytokines and enzymes
COX-2	To convert arachidonic acid to prostaglandins, which are the important inflammatory mediators; the level of prostaglandins is found increased in the frontal cortex of AD patients Its expression is remarkably elevated in the brains of AD patients
5-LOX	Its expression is found elevated in AD brains which has been associated with increased Aβ production and tau phosphorylation Its inhibition can reduce the amyloid and tau pathology as well as to improve cognitive impairment Association with oxidative stress in AD patients
SHIP2	Its inhibition reduces hyperphosphorylation of tau protein by FcγRII receptor

CONCLUSION:

The findings of this systematic review indicate that using Another multi-target technique with a "one compound-multiple targets" approach has evolved as a polypharmacological therapy for Alzheimer's disease. A single medication molecule is developed to target two or more particular proteins involved in the development of AD in this strategy. In addition to knowledge-based and biological screening-based approaches, computational tools are used to aid the design of possible polypharmacological lead molecular scaffolds. Pharmacophore modelling, machine learning, and structure-based virtual screening are increasingly being utilized to predict biological activity and target-ligand interaction for diverse chemical libraries. To obtain the expected activity spectrum of small compounds based on molecular similarities and patterns, both pharmacophore modelling and machine learning use vast bioactivity datasets. Structure-based virtual screening involves computationally screening libraries of compounds against targets with known 3D structures in order to predict the molecular interactions between the target and each chemical component. These computational tools can help you prioritize molecular fragments for the rational design of novel lead molecules^39-47.

CONFLICT OF INTEREST:

The authors have no conflicts of interest or financial.

ACKNOWLEDGMENTS:

The authors would like to thank NCBI, PubMed and Web of Science for the free database services for their kind support during this study.

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Received on 26.12.2022 Modified on 18.07.2023

Asian J. Research Chem. 2024; 17(1):45-49.

DOI: 10.52711/0974-4150.2024.00009