Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

Abstract

<jats:p>Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable <jats:italic>in vitro</jats:italic> properties and on optimized structures that have already been assessed <jats:italic>in vivo</jats:italic> in animal models of dementia.</jats:p>

Tau Oligomers Neurotoxicity

“…It is now becoming increasingly important to believe that multi-target therapy, unlike the current dominant monotherapy, provides more promising results in the treatment of AD [221]. Thus, the concept of multi-targeting ligands (MTDLs) emerged [222]. The basic idea is to create compounds that are combinations of various pharmacophoric elements.…”

Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

“…It is unlikely that targeting a single change will be effective at treating neurodegeneration, as several changes occur in the development of NDs. Given this multifactorial profile, NDs require a multi-target therapeutic approach, and current research is exploring multitarget drugs that can address more than a single event at the same time [44][45][46][47].…”

“…Ultimately, the drug discovery paradigm of NDs has gradually shifted from the design of selective drugs targeting a single pathophysiological pathway toward the development of multitarget agents directed at complex pathophysiological pathways of the diseases [44][45][46][47]. Indeed, the complexity and multiple etiologies of NDs make it challenging to obtain desirable therapeutic effects using single-target drugs.…”

Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

“…The pathophysiological processes in AD have still remained unclear to this day. However, alongside its complexity, several neurodegenerative processes could be identified which include (I) aggregation of insoluble amyloid beta (Aβ) plaques mostly trigger from sequential cleavage of amyloid precursor protein (APP) by the aspartyl protease β-site APP cleaving enzyme-1 (BACE1) and γ-secretase, (II) neurofibrillary tangles (NFTs) form through hyperphosphorylation of tau proteins, (III) biometals dysfunction, and (IV) oxidative stress which in return results in synapse loss and death of neuronal cells in the brain [ 1 ]. Also, different hallmarks have been recognized including the loss of cholinergic neurons, reduction of the neurotransmitter acetylcholine (ACh), and increased expression of inflammatory mediators [ 2 – 4 ].…”