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      Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer's Disease

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          Abstract

          The lack of an adequate therapy for Alzheimer's Disease (AD) contributes greatly to the continuous growing amount of papers and reviews, reflecting the important efforts made by scientists in this field. It is well known that AD is the most common cause of dementia, and up-to-date there is no prevention therapy and no cure for the disease, which contrasts with the enormous efforts put on the task. On the other hand many aspects of AD are currently debated or even unknown. This review offers a view of the current state of knowledge about AD which includes more relevant findings and processes that take part in the disease; it also shows more relevant past, present and future research on therapeutic drugs taking into account the new paradigm “Multi-Target-Directed Ligands” (MTDLs). In our opinion, this paradigm will lead from now on the research toward the discovery of better therapeutic solutions, not only in the case of AD but also in other complex diseases. This review highlights the strategies followed by now, and focuses other emerging targets that should be taken into account for the future development of new MTDLs. Thus, the path followed in this review goes from the pathology and the processes involved in AD to the strategies to consider in on-going and future researches.

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          ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.

          Alzheimer's disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.
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            The cholinergic system in aging and neuronal degeneration.

            The basal forebrain cholinergic complex comprising medial septum, horizontal and vertical diagonal band of Broca, and nucleus basalis of Meynert provides the mayor cholinergic projections to the cerebral cortex and hippocampus. The cholinergic neurons of this complex have been assumed to undergo moderate degenerative changes during aging, resulting in cholinergic hypofunction that has been related to the progressing memory deficits with aging. However, the previous view of significant cholinergic cell loss during aging has been challenged. Neuronal cell loss was found predominantly in pathological aging, such as Alzheimer's disease, while normal aging is accompanied by a gradual loss of cholinergic function caused by dendritic, synaptic, and axonal degeneration as well as a decrease in trophic support. As a consequence, decrements in gene expression, impairments in intracellular signaling, and cytoskeletal transport may mediate cholinergic cell atrophy finally leading to the known age-related functional decline in the brain including aging-associated cognitive impairments. However, in pathological situations associated with cognitive deficits, such as Parkinsons's disease, Down-syndrome, progressive supranuclear palsy, Jakob-Creutzfeld disease, Korsakoff's syndrome, traumatic brain injury, significant degenerations of basal forebrain cholinergic cells have been observed. In presenile (early onset), and in the advanced stages of late-onset Alzheimer's disease (AD), a severe loss of cortical cholinergic innervation has extensively been documented. In contrast, in patients with mild cognitive impairment (MCI, a prodromal stage of AD), and early forms of AD, apparently no cholinergic neurodegeneration but a loss of cholinergic function occurs. In particular imbalances in the expression of NGF, its precursor proNGF, the high and low NGF receptors, trkA and p75NTR, respectively, changes in acetylcholine release, high-affinity choline uptake, as well as alterations in muscarinic and nicotinic acetylcholine receptor expression may contribute to the cholinergic dysfunction. These observations support the suggestion of a key role of the cholinergic system in the functional processes that lead to AD. Malfunction of the cholinergic system may be tackled pharmacologically by intervening in cholinergic as well as neurotrophic signaling cascades that have been shown to ameliorate the cholinergic deficit at early stages of the disease, and slow-down the progression. However, in contrast to many other, dementing disorders, in AD the cholinergic dysfunctions are accompanied by the occurrence of two major histopathological hallmarks such as β-amyloid plaques and neurofibrillary tangles, provoking the question whether they play a particular role in inducing or mediating cholinergic dysfunction in AD. Indeed, there is abundant evidence that β-amyloid may trigger cholinergic dysfunction through action on α7 nicotinic acetylcholine receptors, affecting NGF signaling, mediating tau phosphorylation, interacting with acetylcholinesterase, and specifically affecting the proteome in cholinergic neurons. Therefore, an early onset of an anti β-amyloid strategy may additionally be potential in preventing aging-associated cholinergic deficits and cognitive impairments. Copyright © 2010 Elsevier B.V. All rights reserved.
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              Adenosine receptors as therapeutic targets.

              Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.
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                Author and article information

                Journal
                Curr Neuropharmacol
                Curr Neuropharmacol
                cn
                Current Neuropharmacology
                Bentham Science Publishers
                1570-159X
                1875-6190
                January 2014
                January 2014
                : 12
                : 1
                : 2-36
                Affiliations
                [1 ]Departmental Section of Physiology. Faculty of Pharmacy. Universidad Complutense de Madrid. Madrid 28040, Spain
                [2 ]Department of Organic and Pharmaceutical Chemistry. Faculty of Pharmacy. Universidad Complutense de Madrid 28040, Spain
                [3 ]Biotransformations Group, Universidad Complutense de Madrid 28040, Spain
                Author notes
                [* ]Address correspondence to this author at the Departmental Section of Physiology. Faculty of Pharmacy. Universidad Complutense de Madrid. Madrid 28040, Spain; Tel: +34913941838; E-mail: aagisto@ 123456farm.ucm.es
                Article
                CN-12-2
                10.2174/1570159X113116660047
                3915347
                24533013
                518c2752-1f7e-49e2-a534-75515d5be908
                ©2013 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                : 11 July 2013
                : 20 July 2013
                : 7 October 2013
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                alzheimer's disease,multi-target-directed ligands,hybrid molecules,new molecules design,review.

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