Abstract
Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer′s disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple ligands in drug discovery for AD as a versatile toolbox for a polypharmacological approach to AD. Herein, we highlight major targets associated with AD, ranging from acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3 beta (GSK-3β), N-methyl-d-aspartate (NMDA) receptor, monoamine oxidases (MAOs), metal ions in the brain, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), to phosphodiesterases (PDEs), along with a summary of their respective relationship to the disease network. In addition, a multitarget strategy for AD is presented, based on reported milestones in this area and the recent progress that has been achieved with multitargeted-directed ligands (MTDLs). Finally, the latest publications referencing the enlarged panel of new biological targets for AD related to the microglia are highlighted. However, the question of how to find meaningful combinations of targets for an MTDLs approach remains unanswered.
Highlights
In 1906, Alois Alzheimer presented his first signature case and the pathological features of the disease which, from 1910, became known as Alzheimer’s disease (AD)
AD is a progressive and irreversible neurological disorder occurring in the central nervous system (CNS) mainly confined within the hippocampus and the cerebral cortex, domains of the forebrain related to memory and higher cognitive functions
In the amyloidogenic pathway, GSK-3β inhibition reduces BACE1-mediated cleavage of amyloid precursor protein (APP) through a nuclear factor kappa-light-chain-enhancer of an activated B cell (NF-κB) signaling-mediated mechanism. This observation suggests that the inhibition of GSK-3β reduces Aβ pathology [58,59,60] and GSK-3β plays a key role in choline metabolism, which involves the regulation of choline acetyltransferase (ChAT) and AChE [61,62]
Summary
In 1906, Alois Alzheimer presented his first signature case and the pathological features of the disease which, from 1910, became known as Alzheimer’s disease (AD). In the amyloidogenic pathway, GSK-3β inhibition reduces BACE1-mediated cleavage of APP through a nuclear factor kappa-light-chain-enhancer of an activated B cell (NF-κB) signaling-mediated mechanism. This observation suggests that the inhibition of GSK-3β reduces Aβ pathology [58,59,60] and GSK-3β plays a key role in choline metabolism, which involves the regulation of choline acetyltransferase (ChAT) and AChE [61,62]. The combination therapy of donepezil with cilostazol showed positive effects conclude, there are many biological targets and signalling pathways involved in AD pathology on patients with mild or moderate-to-severe Alzheimer’s patients [91,92].
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