molecules Review Perspectives for New and More Efficient 0 Multifunctional Ligands for Alzheimer s Disease Therapy Agnieszka Zagórska 1,* and Anna Jaromin 2 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland 2 Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, Wroclaw, 50-383 Wrocław, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-12-620-5456 Academic Editor: Barbara Malawska Received: 29 June 2020; Accepted: 21 July 2020; Published: 23 July 2020 Abstract: Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer0s 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. Keywords: multitarget drug discovery; MTDLs; tacrine; donepezil; AChE inhibitors; BACE-1 inhibitors; GSK-3β inhibitors 1. Introduction 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 clinically characterized by a loss of memory, the retardation of thinking and reasoning, and changes in personality and behaviours [1,2]. Nowadays, approximately 40 million people over the age of 60 suffer from AD worldwide, and the number of patients is increasing, with the perspective of cases doubling every 20 years [3]. 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. The histological manifestation of AD presents extracellular deposits of β-amyloid peptide (Aβ) and the intracellular formation of neurofibrillary tangles consisting of paired helical filaments of hyperphosphorylated tau protein [4,5]. AD is a complex and multifactorial disease, which means that it is influenced by a combination of multiple genes and environmental/risk factors. In the early 1990s, mutations in the genes of amyloid-beta A4 precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) were Molecules 2020, 25, 3337; doi:10.3390/molecules25153337 www.mdpi.com/journal/molecules Molecules 2020, 25, 3337 2 of 30 Molecules 2020, 25, x 2 of 34 Molecules 2020, 25, x 2 of 34 Molecules 2020, 25, x 2 of 34 determined for familial AD [6–8]. Presenilins are components of the γ-secretase complex which, when determineddetermined for for familial familial AD AD [6–8]. [6– Presenilins8]. 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Moreover, hypothesis there are [26],neurovascular metal ion hypothesis [[27–29],26], metal and ion lymphatic hypothesis system [27–29 ],hypothesis and lymphatic [30,31]. system Moreover, hypothesis there [30 are,31 ]. [26],many metal factors ion hypothesis that may associated[27–29], and with lymphatic AD, such system as various hypothesis microbes [30,31]. (triggering Moreover, amyloidosis), there are viral manyMoreover, factors there that aremay many associated factors with that mayAD, such associated as various with AD,microbes such (triggering as various microbesamyloidosis), (triggering viral manypathogens factors that (Herpesviridae may associated family) with [32,33], AD, suchdecreased as various expressi microbeson of microRNAs-10 (triggering amyloidosis),7 (miRNA-107) viral [34– pathogensamyloidosis), (Herpesviridae viral pathogens family) (Herpesviridae [32,33], decreasedfamily) expressi [32,33],on decreased of microRNAs-10 expression7 (miRNA-107) of microRNAs-107 [34– pathogens38] and ( HerpesviridaeRAS-RAF-MEK family) signalling [32,33], pathway decreased (atrophy expressi ofon neurons)of microRNAs-10 [39], regional7 (miRNA-107) hypometabolism [34– 38](miRNA-107) and RAS-RAF-MEK [34–38] and signalling RAS-RAF-MEK pathway signalling (atrophy pathwayof neurons) (atrophy [39], regional of neurons)