Future Medicinal Chemistry Research Article part of β -Amyloid-acetylcholine molecular interaction: new role of cholinergic mediators in anti-Alzheimer therapy? M Grimaldi 1 , S Di Marino 1 , F Florenzano 2 , MT Ciotti 3 , SL Nori 4 , M Rodriquez 1 , G Sorrentino 5,6 , AM D’Ursi *,1 & M Scrima* 1 1 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy 2 Confocal Microscopy Unit, EBRI- European Brain Research Institute, Via del Fosso di Fiorano, 64, 00143 Rome, Italy 3 Institute of Cellular Biology & Neurobiology (IBCN), CNR, IRCSS Fondazione Santa Lucia, Via del Fosso di Fiorano 64–65, 00143 Rome, Italy 4 Department of Medicine & Surgery, University of Salerno, Via Allende, 84081 Baronissi (SA), Italy 5 Università degli Studi di Napoli Parthenope, Napoli, Italy 6 Istituto di Diagnosi e Cura Hermitage Capodimonte, Napoli, Italy *Author for correspondence: Tel.: +39 089 969748 Fax: +39 089 969602 dursi@unisa.it Tel +39 089 969176 Fax: +39 089 969602 mscrima@unisa.it Future Med. Chem. (Epub ahead of print) ISSN 1756-8919 10.4155/fmc-2016-0006 © 2016 Future Science Ltd Background: For long time Alzheimer’s disease has been attributed to a cholinergic deficit. More recently, it has been considered dependent on the accumulation of the amyloid beta peptide (Aβ), which promotes neuronal loss and impairs neuronal function. Results/methodology: In the present study, using biophysical and biochemical experiments we tested the hypothesis that in addition to its role as a neurotransmitter, acetylcholine may exert its action as an anti-Alzheimer agent through a direct interaction with Aβ. Conclusion: Our data provide evidence that acetylcholine favors the soluble peptide conformation and exerts a neuroprotective effect against the neuroinflammatory and toxic effects of Aβ. The present paper paves the way toward the development of new polyfunctional anti-Alzheimer therapeutics capable of intervening on both the cholinergic transmission and the Aβ aggregation. First date submitted: 12 January 2016; Accepted for publication: 18 April 2016; Published online: 12 July 2016 Keywords:฀ acetylcholine฀•฀Aβ(25–35)฀•฀Alzheimer’s฀disease฀•฀amyloid฀peptide฀ •฀anti-Alzheimer฀agent฀•฀cholinergic฀trasmission Based on the prevailing idea that many neuropsychiatric diseases are caused by dys- functions in neurotransmission, Alzheimer’s disease (AD) was attributed to a cholinergic deficit due to degeneration of the cholinergic projections from the basal forebrain (nucleus basalis magno cellularis of Meynert) to the cortex and hippocampus until the early 1980s [1] . Subsequently, when it became clear that the pathogenesis of the disease was more complex than a simple neurotransmitter defi- cit, the so-called amyloid cascade hypoth- esis [2] became the main research paradigm in AD pathogenesis. In its first formulation, the amyloid cas- cade hypothesis claims that the formation 15 -5 0 5 10 -15 -10 -20 25 20 190 230 250 210 Wavelength (nm) CD (mdeg) Aβ(2535) - SDS 14 day Aβ(2535) - SDS + Ach 14 day Aβ + Ach Aβ For reprint orders, please contact reprints@future-science.com