We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

β-Amyloid-acetylcholine molecular interaction: new role of cholinergic mediators in anti-Alzheimer therapy?

    Manuela Grimaldi

    Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy

    ,
    Sara Di Marino

    Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy

    ,
    Fulvio Florenzano

    Confocal Microscopy Unit, EBRI-European Brain Research Institute, Via del Fosso di Fiorano, 64, 00143 Rome, Italy

    ,
    Maria Teresa Ciotta

    Institute of Cellular Biology & Neurobiology (IBCN), CNR, IRCSS Fondazione Santa Lucia, Via del Fosso di Fiorano 64–65, 00143 Rome, Italy

    ,
    Stefania Lucia Nori

    Department of Medicine & Surgery, University of Salerno, Via Allende, 84081 Baronissi (SA), Italy

    ,
    Manuela Rodriquez

    Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy

    ,
    Giuseppe Sorrentino

    Università degli Studi di Napoli Parthenope, Napoli, Italy

    Istituto di Diagnosi e Cura Hermitage Capodimonte, Napoli, Italy

    ,
    Anna Maria D'Ursi

    *Author for correspondence:

    E-mail Address: dursi@unisa.it

    ;

    E-mail Address: mscrima@unisa.it

    Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy

    &
    Mario Scrima

    *Author for correspondence:

    E-mail Address: dursi@unisa.it

    ;

    E-mail Address: mscrima@unisa.it

    Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy

    Published Online:https://doi.org/10.4155/fmc-2016-0006

    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.

    Graphical Abstract

    References

    • 1 Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 2(8000), 1403 (1976).
    • 2 Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science 256(5054), 184–185 (1992).
    • 3 Baglioni S, Casamenti F, Bucciantini M et al. Prefibrillar amyloid aggregates could be generic toxins in higher organisms. J. Neurosci. 26(31), 8160–8167 (2006).
    • 4 Lue LF, Kuo YM, Roher AE et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am. J. Pathol. 155(3), 853–862 (1999).
    • 5 Mclean CA, Cherny RA, Fraser FW et al. Soluble pool of A β amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Annu. Rev. Neurosci. 46(6), 860–866 (1999).
    • 6 Kayed R, Pensalfini A, Margol L et al. Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer. J. Biol. Chem. 284(7), 4230–4237 (2009).
    • 7 Khachaturian ZS. Diagnosis of Alzheimer's disease. Arch. Neurol. 42(11), 1097–1105 (1985).
    • 8 Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat. Rev. Mol. Cell Biol. 8(2), 101–112 (2007).
    • 9 Picone P, Carrotta R, Montana G, Nobile MR, San Biagio PL, Di Carlo M. Abeta oligomers and fibrillar aggregates induce different apoptotic pathways in LAN5 neuroblastoma cell cultures. Biophys. J. 96(10), 4200–4211 (2009).
    • 10 Stains CI, Mondal K, Ghosh I. Molecules that target beta-amyloid. ChemMedChem 2(12), 1674–1692 (2007).
    • 11 Hamley IW. The amyloid beta peptide: a chemist's perspective. Role in Alzheimer's and fibrillization. Chem. Rev. 112(10), 5147–5192 (2012).
    • 12 Nasica-Labouze J, Nguyen PH, Sterpone F et al. Amyloid beta protein and Alzheimer's disease: when computer simulations complement experimental studies. Chem. Rev. 115(9), 3518–3563 (2015).
    • 13 Campiglia P, Esposito C, Scrima M et al. Conformational stability of A beta-(25–35) in the presence of thiazolidine derivatives. Chem. Biol. Drug Des. 69(2), 111–118 (2007).
    • 14 Campiglia P, Scrima M, Grimaldi M et al. A new series of 1,3-dihidro-imidazo 1,5-c thiazole-5,7-dione derivatives: synthesis and interaction with A beta(25–35) amyloid peptide. Chem. Biol. Drug Des. 74(3), 224–233 (2009).
    • 15 Vitiello G, Grimaldi M, D'Ursi AM, D'Errico G. The iA beta 5p beta-breaker peptide regulates the A beta(25–35) interaction with lipid bilayers through a cholesterol-mediated mechanism. Biochem. Biophys. Res. Commun. 417(1), 88–92 (2012).
    • 16 Saponetti MS, Grimaldi M, Scrima M et al. Aggregation of A beta(25–35) on DOPC and DOPC/DHA bilayers: an atomic force microscopy study. PLoS ONE 9(12), (2014).
    • 17 Esposito C, Tedeschi A, Scrima M et al. Exploring interaction of beta-amyloid segment (25–35) with membrane models through paramagnetic probes. J. Pept. Sci. 12(12), 766–774 (2006).
    • 18 Pike CJ, Walencewicz-Wasserman AJ, Kosmoski J, Cribbs DH, Glabe CG, Cotman CW. Structure–activity analyses of beta-amyloid peptides: contributions of the beta 25–35 region to aggregation and neurotoxicity. J. Neurochem. 64(1), 253–265 (1995).
    • 19 Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW. Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J. Neurosci. 13(4), 1676–1687 (1993).
    • 20 Terzi E, Hoelzemann G, Seelig J. Alzheimer beta-amyloid peptide 25–35: electrostatic interactions with phospholipid membranes. Biochemistry 33(23), 7434–7441 (1994).
    • 21 Bartus RT. On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp. Neurol. 163(2), 495–529 (2000).
    • 22 Craig LA, Hong NS, Mcdonald RJ. Revisiting the cholinergic in the development of Alzheimer's disease. Neurosci. Biobehav. Rev. 35(6), 1397–1409 (2011).
    • 23 Prasansuklab A, Tencomnao T. Amyloidosis in Alzheimer's disease: the toxicity of amyloid Beta (A beta), mechanisms of its accumulation and implications of medicinal plants for therapy. Evid. Based Complement. Alternat. Med. 2013, 413808 (2013).
    • 24 Pedersen WA, Kloczewiak MA, Blusztajn JK. Amyloid beta-protein reduces acetylcholine synthesis in a cell line derived from cholinergic neurons of the basal forebrain. Proc. Natl Acad. Sci. USA 93(15), 8068–8071 (1996).
    • 25 Kar S, Seto D, Gaudreau P, Quirion R. Beta-amyloid-related peptides inhibit potassium-evoked acetylcholine release from rat hippocampal slices. J. Neurosci. 16(3), 1034–1040 (1996).
    • 26 Vaucher E, Aumont N, Pearson D, Rowe W, Poirier J, Kar S. Amyloid beta peptide levels and its effects on hippocampal acetylcholine release in aged, cognitively-impaired and -unimpaired rats. J. Chem. Neuroanat. 21(4), 323–329 (2001).
    • 27 Ehrenstein G, Galdzicki Z, Lange GD. The choline-leakage hypothesis for the loss of acetylcholine in Alzheimer's disease. Biophys. J. 73(3), 1276–1280 (1997).
    • 28 Nitsch RM, Slack BE, Wurtman RJ, Growdon JH. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258(5080), 304–307 (1992).
    • 29 Lin L, Georgievska B, Mattsson A, Isacson O. Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation. Proc. Natl Acad. Sci. USA 96(21), 12108–12113 (1999).
    • 30 Aztiria E, Cataudella T, Spampinato S, Leanza G. Septal grafts restore cognitive abilities and amyloid precursor protein metabolism. Neurobiol. Aging 30(10), 1614–1625 (2009).
    • 31 Antonini V, Marrazzo A, Kleiner G et al. Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion. J. Alzheimer's Dis. 24(3), 569–586 (2011).
    • 32 Sorrentino P, Iuliano A, Polverino A, Jacini F, Sorrentino G. The dark sides of amyloid in Alzheimer's disease pathogenesis. FEBS Lett. 588(5), 641–652 (2014).
    • 33 Wattmo C, Wallin AK, Minthon L. Functional response to cholinesterase inhibitor therapy in a naturalistic Alzheimer's disease cohort. BMC Neurol. 12, 134 (2012).
    • 34 Viayna E, Sabate R, Munoz-Torrero D. Dual inhibitors of beta-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates. Curr. Top. Med. Chem. 13(15), 1820–1842 (2013).
    • 35 Shaik JB, Palaka BK, Penumala M et al. Synthesis, biological evaluation and molecular docking of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene analogues: new dual AChE inhibitors as potential drugs for the treatment of Alzheimers disease. Chem. Biol. Drug Des. 88(1), 43–53 (2016).
    • 36 Ambure P, Roy K. CADD modeling of multi-target drugs against Alzheimer's disease. Curr. Drug Targets (2015) (Epub ahead of print).
    • 37 Dinamarca MC, Sagal JP, Quintanilla RA, Godoy JA, Arrazola MS, Inestrosa NC. Amyloid-beta-acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Abeta peptide. Implications for the pathogenesis of Alzheimer's disease. Mol. Neurodegener. 5, 4 (2010).
    • 38 Zagorski MG, Yang J, Shao H, Ma K, Zeng H, Hong A. Methodological and chemical factors affecting amyloid beta peptide amyloidogenicity. Methods Enzymol. 309, 189–204 (1999).
    • 39 Whitmore L, Wallace BA. DICHROWEB, an online server for protein secondary structure analyses from circular dichroism spectroscopic data. Nucleic Acids Res. 32, W668–W673 (2004).
    • 40 Kotler SA, Walsh P, Brender JR, Ramamoorthy A. Differences between amyloid-β aggregation in solution and on the membrane: insights into elucidation of the mechanistic details of Alzheimer's disease. Chem. Soc. Rev. 43(19), 6692–6700 (2014).
    • 41 Grimaldi M, Scrima M, Esposito C et al. Membrane charge dependent states of the beta-amyloid fragment Abeta (16–35) with differently charged micelle aggregates. Biochim. Biophys. Acta 1798(3), 660–671 (2010).
    • 42 D'Ursi AM, Armenante MR, Guerrini R, Salvadori S, Sorrentino G, Picone D. Solution structure of amyloid beta-peptide (25–35) in different media. J. Med. Chem. 47(17), 4231–4238 (2004).
    • 43 Severini C, Passeri PP, Ciotti M et al. Bindarit, inhibitor of CCL2 synthesis, protects neurons against amyloid-beta-induced toxicity. J. Alzheimer's Dis. 38(2), 281–293 (2014).
    • 44 Pimplikar SW. Neuroinflammation in Alzheimer's disease: from pathogenesis to a therapeutic target. J. Clin. Immunol. 34, S64–S69 (2014).
    • 45 Rodríguez-Arellano JJ, Parpura V, Zorec R, Verkhratsky A. Astrocytes in physiological aging and Alzheimer's disease. Neuroscience 323, 170–182 (2015).
    • 46 Nagele RG, D'andrea MR, Lee H, Venkataraman V, Wang HY. Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 971(2), 197–209 (2003).
    • 47 Tarkowski E, Liljeroth A-M, Minthon L, Tarkowski A, Wallin A, Blennow K. Cerebral pattern of pro-and anti-inflammatory cytokines in dementias. Brain Res. Bull. 61(3), 255–260 (2003).
    • 48 Singh I, Sorrentino G, Sitar D, Kanfer J. Indomethacin and nordihydroguaiaretic acid inhibition of amyloid β protein (25–35) activation of phospholipases A 2 and D of LA-N-2 cells. Neurosci. Lett. 222(1), 5–8 (1997).
    • 49 Desbène C, Malaplate-Armand C, Youssef I et al. Critical role of cPLA 2 in A β oligomer-induced neurodegeneration and memory deficit. Neurobiol. Aging 33(6), 1123.e1117–1123.e1129 (2012).
    • 50 Wood SJ, Mackenzie L, Maleeff B, Hurle MR, Wetzel R. Selective inhibition of Abeta fibril formation. J. Biol. Chem. 271(8), 4086–4092 (1996).
    • 51 Ryan TM, Friedhuber A, Lind M, Howlett GJ, Masters C, Roberts BR. Small amphipathic molecules modulate secondary structure and amyloid fibril-forming kinetics of Alzheimer disease peptide Abeta(1–42). J. Biol. Chem. 287(20), 16947–16954 (2012).
    • 52 Vitiello G, Grimaldi M, Ramunno A et al. Interaction of a beta-sheet breaker peptide with lipid membranes. J. Pept. Sci. 16(2), 115–122 (2010).
    • 53 D'errico G, Vitiello G, Ortona O, Tedeschi A, Ramunno A, D'ursi AM. Interaction between Alzheimer's A beta(25–35) peptide and phospholipid bilayers: the role of cholesterol. Biochim. Biophys. Acta 1778(12), 2710–2716 (2008).
    • 54 Jao SC, Ma K, Talafous J, Orlando R, Zagorski MG. Trifluoroacetic acid pretreatment reproducibly disaggregates the amyloid beta-peptide. J. Exp. Clin. Cancer Res. 4(4), 240–252 (1997).
    • 55 Culmsee C, Gerling N, Lehmann M et al. Nerve growth factor survival signaling in cultured hippocampal neurons is mediated through TRKA and requires the common neurotrophin receptor p75. Neuroscience 115(4), 1089–1108 (2002).
    • 56 Volonte C, Ciotti MT, Battistini L. Development of a method for measuring cell number: application to CNS primary neuronal cultures. Cytometry 17(3), 274–276 (1994).