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Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: a new therapeutic perspective in aging-related disorders

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Abstract

Neuroinflammation and cholinergic dysfunction, leading to cognitive impairment, are hallmarks of aging and neurodegenerative disorders, including Alzheimer’s disease (AD). Acetylcholinesterase inhibitors (AChEI), the symptomatic therapy in AD, attenuate and delay the cognitive deficit by enhancing cholinergic synapses. The α7 nicotinic acetylcholine (ACh) receptor has shown a double-edged sword feature, as it binds with high affinity Aβ1–42, promoting intracellular accumulation and Aβ-induced tau phosphorylation, but also exerts neuroprotection by stimulating anti-apoptotic pathways. Moreover, it mediates peripheral and central anti-inflammatory response, being the effector player of the activation of the cholinergic anti-inflammatory pathway (CAIP), that, by decreasing the release of TNF-α, IL-1β, and IL-6, it may have a role in improving cognition. The finding in preclinical models that, in addition to their major function (choline esterase inhibition) AChEIs have neuroprotective properties mediated via α7nAChR and modulate innate immunity, possibly as a result of the increased availability of acetylcholine activating the CAIP, pave the way for new pharmacological intervention in AD and other neurological disorders that are characterized by neuroinflammation. CHRFAM7A is a human-specific gene acting as a dominant negative inhibitor of α7nAChR function, also suggesting a role in affecting human cognition and memory by altering α7nAChR activities in the central nervous system (CNS). This review will summarize the current knowledge on the cholinergic anti-inflammatory pathway in aging-related disorders, and will argue that the presence of the human-restricted CHRFAM7A gene might play a fundamental role in the regulation of CAIP and in the response to AChEI.

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References

  1. Niraula A, Sheridan JF, Godbout JP (2017) Microglia priming with aging and stress. Neuropsychopharmacology 42:318–333. https://doi.org/10.1038/npp.2016.185

    Article  PubMed  Google Scholar 

  2. Schliebs R, Arendt T (2011) The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221:555–563. https://doi.org/10.1016/j.bbr.2010.11.058

    Article  CAS  PubMed  Google Scholar 

  3. Heneka MT, Carson MJ, El Khoury J et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405. https://doi.org/10.1016/S1474-4422(15)70016-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sinkus ML, Graw S, Freedman R (2015) The human CHRNA7 and CHRFAM7A genes: a review of the genetics, regulation, and function. Neuropharmacology 96:274–288. https://doi.org/10.1016/j.neuropharm.2015.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tracey KJ (2002) The inflammatory reflex. Nature 420:853. https://doi.org/10.1038/nature01321

    Article  CAS  PubMed  Google Scholar 

  6. Confaloni A, Tosto G, Tata AM (2016) Promising therapies for Alzheimer’s disease. Curr Pharm Des 22:2050–2056

    Article  CAS  PubMed  Google Scholar 

  7. Hoskin JL, Al-Hasan Y, Sabbagh MN (2019) Nicotinic acetylcholine receptor agonists for the treatment of Alzheimer’s dementia: an update. Nicotine Tob Res 21:370–376. https://doi.org/10.1093/ntr/nty116

    Article  PubMed  Google Scholar 

  8. Akaike A, Takada-Takatori Y, Kume T et al (2010) Mechanisms of neuroprotective effects of nicotine and acetylcholinesterase inhibitors: role of alpha4 and alpha7 receptors in neuroprotection. J Mol Neurosci 40:211–216. https://doi.org/10.1007/s12031-009-9236-1

    Article  CAS  PubMed  Google Scholar 

  9. Pavlov VA, Parrish WR, Rosas-Ballina M et al (2009) Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav Immun 23:41–45. https://doi.org/10.1016/j.bbi.2008.06.011

    Article  CAS  PubMed  Google Scholar 

  10. Pohanka M (2014) Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity. Int J Mol Sci 15:9809–9825. https://doi.org/10.3390/ijms15069809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Reale M, Iarlori C, Gambi F et al (2004) Treatment with an acetylcholinesterase inhibitor in Alzheimer patients modulates the expression and production of the pro-inflammatory and anti-inflammatory cytokines. J Neuroimmunol 148:162–171. https://doi.org/10.1016/j.jneuroim.2003.11.003

    Article  CAS  PubMed  Google Scholar 

  12. Counts SE, He B, Che S et al (2007) Alpha7 nicotinic receptor up-regulation in cholinergic basal forebrain neurons in Alzheimer disease. Arch Neurol 64:1771–1776. https://doi.org/10.1001/archneur.64.12.1771

    Article  PubMed  Google Scholar 

  13. Carson R, Craig D, McGuinness B et al (2008) Alpha7 nicotinic acetylcholine receptor gene and reduced risk of Alzheimer’s disease. J Med Genet 45:244–248. https://doi.org/10.1136/jmg.2007.052704

    Article  CAS  PubMed  Google Scholar 

  14. Chu LW, Ma ES, Lam KK et al (2005) Increased alpha 7 nicotinic acetylcholine receptor protein levels in Alzheimer’s disease patients. Dement Geriatr Cogn Disord 19:106–112. https://doi.org/10.1159/000082661

    Article  CAS  PubMed  Google Scholar 

  15. Weng PH, Chen JH, Chen TF et al (2013) CHRNA7 polymorphisms and response to cholinesterase inhibitors in Alzheimer’s disease. PLoS ONE 8:e84059. https://doi.org/10.1371/journal.pone.0084059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lasala M, Corradi J, Bruzzone A et al (2018) A human-specific, truncated alpha7 nicotinic receptor subunit assembles with full-length alpha7 and forms functional receptors with different stoichiometries. J Biol Chem 293:10707–10717. https://doi.org/10.1074/jbc.RA117.001698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. de Lucas-Cerrillo AM, Maldifassi MC, Arnalich F et al (2011) Function of partially duplicated human α77 nicotinic receptor subunit CHRFAM7A gene: potential implications for the cholinergic anti-inflammatory response. J Biol Chem 286:594–606. https://doi.org/10.1074/jbc.M110.180067

    Article  CAS  PubMed  Google Scholar 

  18. Costantini TW, Chan TW, Cohen O et al (2019) Uniquely human CHRFAM7A gene increases the hematopoietic stem cell reservoir in mice and amplifies their inflammatory response. Proc Natl Acad Sci USA 116:7932–7940. https://doi.org/10.1073/pnas.1821853116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Maldifassi MC, Martín-Sánchez C, Atienza G et al (2018) Interaction of the α7-nicotinic subunit with its human-specific duplicated dupα7 isoform in mammalian cells: relevance in human inflammatory responses. J Biol Chem 293:13874–13888. https://doi.org/10.1074/jbc.RA118.003443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dang X, Eliceiri BP, Baird A et al (2015) CHRFAM7A: a human-specific α7-nicotinic acetylcholine receptor gene shows differential responsiveness of human intestinal epithelial cells to LPS. FASEB J 29:2292–2302. https://doi.org/10.1096/fj.14-268037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Borovikova LV, Ivanova S, Zhang M et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462. https://doi.org/10.1038/35013070

    Article  CAS  PubMed  Google Scholar 

  22. Hoover DB (2017) Cholinergic modulation of the immune system presents new approaches for treating inflammation. Pharmacol Ther 179:1–16. https://doi.org/10.1016/j.pharmthera.2017.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Eglen RM (2012) Overview of muscarinic receptor subtypes. Handb Exp Pharmacol 208:3–28. https://doi.org/10.1007/978-3-642-23274-9_1

    Article  CAS  Google Scholar 

  24. Albuquerque EX, Pereira EF, Alkondon M et al (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89:73–120. https://doi.org/10.1152/physrev.00015.2008

    Article  CAS  PubMed  Google Scholar 

  25. Zoli M, Pucci S, Vilella A et al (2018) Neuronal and extraneuronal nicotinic acetylcholine receptors. Curr Neuropharmacol 16:338–349. https://doi.org/10.2174/1570159X15666170912110450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang H, Yu M, Ochani M et al (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384–388. https://doi.org/10.1038/nature01339

    Article  CAS  PubMed  Google Scholar 

  27. Eduardo CC, Alejandra TG, Guadalupe DKJ (2019) Modulation of the extraneuronal cholinergic system on main innate response leukocytes. J Neuroimmunol 327:22–35. https://doi.org/10.1016/j.jneuroim.2019.01.008

    Article  CAS  PubMed  Google Scholar 

  28. Kabbani N, Nichols RA (2018) Beyond the channel: metabotropic signaling by nicotinic receptors. Trends Pharmacol Sci 39:354–366. https://doi.org/10.1016/j.tips.2018.01.002

    Article  CAS  PubMed  Google Scholar 

  29. Chang KT, Berg DK (2001) Voltage-gated channels block nicotinic regulation of CREB phosphorylation and gene expression in neurons. Neuron 32:855–865

    Article  CAS  PubMed  Google Scholar 

  30. Berg DK, Conroy WG (2002) Nicotinic alpha 7 receptors: synaptic options and downstream signaling in neurons. J Neurobiol 53:512–523. https://doi.org/10.1002/neu.10116

    Article  CAS  PubMed  Google Scholar 

  31. Sharma G, Vijayaraghavan S (2002) Nicotinic receptor signaling in nonexcitable cells. J Neurobiol 53:524–534. https://doi.org/10.1002/neu.10114

    Article  CAS  PubMed  Google Scholar 

  32. Shytle RD, Mori T, Townsend K et al (2004) Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 89:337–343. https://doi.org/10.1046/j.1471-4159.2004.02347.x

    Article  CAS  PubMed  Google Scholar 

  33. King JR, Gillevet TC, Kabbani N (2017) A G protein-coupled alpha7 nicotinic receptor regulates signaling and TNF-alpha release in microglia. FEBS Open Bio 7:1350–1361. https://doi.org/10.1002/2211-5463.12270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Suzuki T, Hide I, Matsubara A et al (2006) Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. J Neurosci Res 83:1461–1470. https://doi.org/10.1002/jnr.20850

    Article  CAS  PubMed  Google Scholar 

  35. Richter K, Sagawe S, Hecker A et al (2018) C-reactive protein stimulates nicotinic acetylcholine receptors to control ATP-mediated monocytic inflammasome activation. Front Immunol 9:1604. https://doi.org/10.3389/fimmu.2018.01604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Razani-Boroujerdi S, Boyd RT, Dávila-García MI et al (2007) T cells express alpha7-nicotinic acetylcholine receptor subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ response. J Immunol 179:2889–2898. https://doi.org/10.4049/jimmunol.179.5.2889

    Article  CAS  PubMed  Google Scholar 

  37. Stokes C, Treinin M, Papke RL (2015) Looking below the surface of nicotinic acetylcholine receptors. Trends Pharmacol Sci 36:514–523. https://doi.org/10.1016/j.tips.2015.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Marrero MB, Bencherif M (2009) Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: central role for JAK2 activation of STAT3 and NF-kappaB. Brain Res 1256:1–7. https://doi.org/10.1016/j.brainres.2008.11.053

    Article  CAS  PubMed  Google Scholar 

  39. de Jonge WJ, van der Zanden EP, The FO et al (2005) Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 6:844–851. https://doi.org/10.1038/ni1229

    Article  CAS  PubMed  Google Scholar 

  40. Shaw S, Bencherif M, Marrero MB (2002) Janus kinase 2, an early target of alpha 7 nicotinic acetylcholine receptor-mediated neuroprotection against Abeta-(1-42) amyloid. J Biol Chem 277:44920–44924. https://doi.org/10.1074/jbc.M204610200

    Article  CAS  PubMed  Google Scholar 

  41. Yoshikawa H, Kurokawa M, Ozaki N et al (2006) Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7. Clin Exp Immunol 146:116–123. https://doi.org/10.1111/j.1365-2249.2006.03169.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Patel H, McIntire J, Ryan S et al (2017) Anti-inflammatory effects of astroglial alpha7 nicotinic acetylcholine receptors are mediated by inhibition of the NF-kappaB pathway and activation of the Nrf2 pathway. J Neuroinflammation 14:192. https://doi.org/10.1186/s12974-017-0967-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sun Y, Li Q, Gui H et al (2013) MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines. Cell Res 23:1270–1283. https://doi.org/10.1038/cr.2013.116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Maldifassi MC, Atienza G, Arnalich F et al (2014) A new IRAK-M-mediated mechanism implicated in the anti-inflammatory effect of nicotine via α7 nicotinic receptors in human macrophages. PLoS ONE 9:e108397. https://doi.org/10.1371/journal.pone.0108397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Takahashi T, Morrow JD, Wang H et al (2006) Cyclooxygenase-2-derived prostaglandin E(2) directs oocyte maturation by differentially influencing multiple signaling pathways. J Biol Chem 281:37117–37129. https://doi.org/10.1074/jbc.M608202200

    Article  CAS  PubMed  Google Scholar 

  46. Neri M, Bonassi S, Russo P (2012) Genetic variations in CHRNA7 or CHRFAM7 and susceptibility to dementia. Curr Drug Targets 13:636–643

    Article  PubMed  Google Scholar 

  47. Wang HY, Lee DH, D’Andrea MR, Peterson PA, Shank RP, Reitz AB (2000) beta-Amyloid(1–42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology. J Biol Chem 275:5626–5632. https://doi.org/10.1074/jbc.275.8.5626

    Article  CAS  PubMed  Google Scholar 

  48. Dziewczapolski G, Glogowski CM, Masliah E et al (2009) Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer’s disease. J Neurosci 29:8805–8815. https://doi.org/10.1523/JNEUROSCI.6159-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nagele RG, D’Andrea MR, Anderson WJ et al (2002) Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer’s disease. Neuroscience 110:199–211

    Article  CAS  PubMed  Google Scholar 

  50. Wang HY, Li W, Benedetti NJ et al (2003) Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. J Biol Chem 278:31547–31553. https://doi.org/10.1074/jbc.M212532200

    Article  CAS  PubMed  Google Scholar 

  51. Pettit DL, Shao Z, Yakel JL (2001) beta-Amyloid(1-42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. J Neurosci 21:120

    Article  Google Scholar 

  52. Park HJ, Lee PH, Ahn YW et al (2007) Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. Eur J Neurosci 26:79–89. https://doi.org/10.1111/j.1460-9568.2007.05636.x

    Article  PubMed  Google Scholar 

  53. Heneka MT, Kummer MP, Latz E (2014) Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14:463–477. https://doi.org/10.1038/nri3705

    Article  CAS  PubMed  Google Scholar 

  54. Egea J, Buendia I, Parada E et al (2015) Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. Biochem Pharmacol 97:463–472. https://doi.org/10.1016/j.bcp.2015.07.032

    Article  CAS  PubMed  Google Scholar 

  55. De Simone R, Ajmone-Cat MA, Carnevale D et al (2005) Activation of alpha7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures. J Neuroinflammation 2:4. https://doi.org/10.1186/1742-2094-2-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Benfante R, Antonini RA, De Pizzol M et al (2011) Expression of the α7 nAChR subunit duplicate form (CHRFAM7A) is down-regulated in the monocytic cell line THP-1 on treatment with LPS. J Neuroimmunol 230:74–84. https://doi.org/10.1016/j.jneuroim.2010.09.008

    Article  CAS  PubMed  Google Scholar 

  57. Villiger Y, Szanto I, Jaconi S et al (2002) Expression of an alpha7 duplicate nicotinic acetylcholine receptor-related protein in human leukocytes. J Neuroimmunol 126:86–98

    Article  CAS  PubMed  Google Scholar 

  58. Maroli A, Di Lascio S, Drufuca L et al (2019) Effect of donepezil on the expression and responsiveness to LPS of CHRNA7 and CHRFAM7A in macrophages: a possible link to the cholinergic anti-inflammatory pathway. J Neuroimmunol 332:155–166. https://doi.org/10.1016/j.jneuroim.2019.04.012

    Article  CAS  PubMed  Google Scholar 

  59. Yasui DH, Scoles HA, Horike S, Meguro-Horike M, Dunaway KW, Schroeder DI, Lasalle JM (2011) 15q11.2-13.3 chromatin analysis reveals epigenetic regulation of CHRNA7 with deficiencies in Rett and autism brain. Hum Mol Genet 20:4311–4323. https://doi.org/10.1093/hmg/ddr357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kunii Y, Zhang W, Xu Q et al (2015) CHRNA7 and CHRFAM7A mRNAs: co-localized and their expression levels altered in the postmortem dorsolateral prefrontal cortex in major psychiatric disorders. Am J Psychiatry 172:1122–1130. https://doi.org/10.1176/appi.ajp.2015.14080978

    Article  PubMed  Google Scholar 

  61. Mucchietto V, Fasoli F, Pucci S et al (2018) α9- and α7-containing receptors mediate the pro-proliferative effects of nicotine in the A549 adenocarcinoma cell line. Br J Pharmacol 175:1957–1972. https://doi.org/10.1111/bph.13954

    Article  CAS  PubMed  Google Scholar 

  62. Araud T, Graw S, Berger R et al (2011) The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of α7*nAChR function. Biochem Pharmacol 82:904–914. https://doi.org/10.1016/j.bcp.2011.06.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang Y, Xiao C, Indersmitten T et al (2014) The duplicated α7 subunits assemble and form functional nicotinic receptors with the full-length α7. J Biol Chem 289:26451–26463. https://doi.org/10.1074/jbc.M114.582858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rozycka A, Dorszewska J, Steinborn B et al (2013) A transcript coding for a partially duplicated form of α7 nicotinic acetylcholine receptor is absent from the CD4+ T-lymphocytes of patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Folia Neuropathol 51:65–75

    Article  CAS  PubMed  Google Scholar 

  65. Swaminathan S, Kim S, Shen L et al (2011) Genomic copy number analysis in Alzheimer’s disease and mild cognitive impairment: an ADNI study. Int J Alzheimers Dis 2011:729478. https://doi.org/10.4061/2011/729478

    Article  PubMed  PubMed Central  Google Scholar 

  66. Fehér A, Juhász A, Rimanóczy A et al (2009) Association between a genetic variant of the alpha-7 nicotinic acetylcholine receptor subunit and four types of dementia. Dement Geriatr Cogn Disord 28:56–62. https://doi.org/10.1159/000230036

    Article  CAS  PubMed  Google Scholar 

  67. Iadecola C (2013) The pathobiology of vascular dementia. Neuron 80:844–866. https://doi.org/10.1016/j.neuron.2013.10.008

    Article  CAS  PubMed  Google Scholar 

  68. Ramos FM, Delgado-Vélez M, Ortiz Á et al (2016) Expression of CHRFAM7A and CHRNA7 in neuronal cells and postmortem brain of HIV-infected patients: considerations for HIV-associated neurocognitive disorder. J Neurovirol 22:327–335. https://doi.org/10.1007/s13365-015-0401-8

    Article  CAS  PubMed  Google Scholar 

  69. Costantini TW, Dang X, Coimbra R et al (2015) CHRFAM7A, a human-specific and partially duplicated α7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury. J Leukoc Biol 97:247–257. https://doi.org/10.1189/jlb.4RU0814-381R

    Article  CAS  PubMed  Google Scholar 

  70. Baird A, Coimbra R, Dang X et al (2016) Up-regulation of the human-specific CHRFAM7A gene in inflammatory bowel disease. BBA Clin 5:66–71. https://doi.org/10.1016/j.bbacli.2015.12.003

    Article  PubMed  PubMed Central  Google Scholar 

  71. Colovic MB, Krstic DZ, Lazarevic-Pasti TD et al (2013) Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 11:315–335. https://doi.org/10.2174/1570159X11311030006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Han SH, Park JC, Byun MS et al (2019) Blood acetylcholinesterase level is a potential biomarker for the early detection of cerebral amyloid deposition in cognitively normal individuals. Neurobiol Aging 73:21–29. https://doi.org/10.1016/j.neurobiolaging.2018.09.001

    Article  CAS  PubMed  Google Scholar 

  73. Fodero LR, Mok SS, Losic D et al (2004) Alpha7-nicotinic acetylcholine receptors mediate an Abeta(1-42)-induced increase in the level of acetylcholinesterase in primary cortical neurones. J Neurochem 88:1186–1193. https://doi.org/10.1046/j.1471-4159.2003.02296.x

    Article  CAS  PubMed  Google Scholar 

  74. Inestrosa NC, Dinamarca MC, Alvarez A (2008) Amyloid-cholinesterase interactions. Implications for Alzheimer’s disease. FEBS J 275:625–632. https://doi.org/10.1111/j.1742-4658.2007.06238.x

    Article  CAS  PubMed  Google Scholar 

  75. Reale M, Di Nicola M, Velluto L et al (2014) Selective acetyl- and butyrylcholinesterase inhibitors reduce amyloid-β ex vivo activation of peripheral chemo-cytokines from Alzheimer’s disease subjects: exploring the cholinergic anti-inflammatory pathway. Curr Alzheimer Res 11:608–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Clarelli F, Mascia E, Santangelo R et al (2016) CHRNA7 gene and response to cholinesterase inhibitors in an Italian cohort of Alzheimer’s disease patients. J Alzheimers Dis 52:1203–1208. https://doi.org/10.3233/JAD-160074

    Article  CAS  PubMed  Google Scholar 

  77. Braga IL, Silva PN, Furuya TK et al (2015) Effect of APOE and CHRNA7 genotypes on the cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer’s disease. Am J Alzheimers Dis Other Demen 30:139–144. https://doi.org/10.1177/1533317514539540

    Article  PubMed  Google Scholar 

  78. Russo P, Kisialiou A, Moroni R et al (2017) Effect of genetic polymorphisms (SNPs) in CHRNA7 gene on response to acetylcholinesterase inhibitors (AChEI) in patients with Alzheimer’s disease. Curr Drug Targets 18:1179–1190

    CAS  PubMed  Google Scholar 

  79. Tyagi E, Agrawal R, Nath C et al (2010) Cholinergic protection via alpha7 nicotinic acetylcholine receptors and PI3K-Akt pathway in LPS-induced neuroinflammation. Neurochem Int 56:135–142. https://doi.org/10.1016/j.neuint.2009.09.011

    Article  CAS  PubMed  Google Scholar 

  80. Noh MY, Koh SH, Kim SM et al (2013) Neuroprotective effects of donepezil against Abeta42-induced neuronal toxicity are mediated through not only enhancing PP2A activity but also regulating GSK-3beta and nAChRs activity. J Neurochem 127:562–574. https://doi.org/10.1111/jnc.12319

    Article  CAS  PubMed  Google Scholar 

  81. Tabet N (2006) Acetylcholinesterase inhibitors for Alzheimer’s disease: anti-inflammatories in acetylcholine clothing! Age Ageing 35:336–338. https://doi.org/10.1093/ageing/afl027

    Article  CAS  PubMed  Google Scholar 

  82. Arias E, Alés E, Gabilan NH et al (2004) Galantamine prevents apoptosis induced by beta-amyloid and thapsigargin: involvement of nicotinic acetylcholine receptors. Neuropharmacology 46:103–114

    Article  CAS  PubMed  Google Scholar 

  83. Kim SH, Kandiah N, Hsu JL et al (2017) Beyond symptomatic effects: potential of donepezil as a neuroprotective agent and disease modifier in Alzheimer’s disease. Br J Pharmacol 174:4224–4232. https://doi.org/10.1111/bph.14030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kimura M, Akasofu S, Ogura H et al (2005) Protective effect of donepezil against Abeta(1-40) neurotoxicity in rat septal neurons. Brain Res 1047:72–84. https://doi.org/10.1016/j.brainres.2005.04.014

    Article  CAS  PubMed  Google Scholar 

  85. Nizri E, Hamra-Amitay Y, Sicsic C et al (2006) Anti-inflammatory properties of cholinergic up-regulation: a new role for acetylcholinesterase inhibitors. Neuropharmacology 50:540–547. https://doi.org/10.1016/j.neuropharm.2005.10.013

    Article  CAS  PubMed  Google Scholar 

  86. Pollak Y, Gilboa A, Ben-Menachem O et al (2005) Acetylcholinesterase inhibitors reduce brain and blood interleukin-1beta production. Ann Neurol 57:741–745. https://doi.org/10.1002/ana.20454

    Article  CAS  PubMed  Google Scholar 

  87. Reale M, Iarlori C, Gambi F et al (2006) The acetylcholinesterase inhibitor, Donepezil, regulates a Th2 bias in Alzheimer’s disease patients. Neuropharmacology 50:606–613. https://doi.org/10.1016/j.neuropharm.2005.11.006

    Article  CAS  PubMed  Google Scholar 

  88. Conti E, Galimberti G, Tremolizzo L et al (2010) Cholinesterase inhibitor use is associated with increased plasma levels of anti-Abeta 1-42 antibodies in Alzheimer’s disease patients. Neurosci Lett 486:193–196. https://doi.org/10.1016/j.neulet.2010.09.050

    Article  CAS  PubMed  Google Scholar 

  89. Imamura O, Arai M, Dateki M et al (2015) Nicotinic acetylcholine receptors mediate donepezil-induced oligodendrocyte differentiation. J Neurochem 135:1086–1098. https://doi.org/10.1111/jnc.13294

    Article  CAS  PubMed  Google Scholar 

  90. Ludwig J, Höffle-Maas A, Samochocki M et al (2010) Localization by site-directed mutagenesis of a galantamine binding site on α7 nicotinic acetylcholine receptor extracellular domain. J Recept Signal Transduct Res 30:469–483. https://doi.org/10.3109/10799893.2010.505239

    Article  CAS  PubMed  Google Scholar 

  91. Samochocki M, Höffle A, Fehrenbacher A et al (2003) Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther 305:1024–1036. https://doi.org/10.1124/jpet.102.045773

    Article  CAS  PubMed  Google Scholar 

  92. Kowal NM, Ahring PK, Liao VWY et al (2018) Galantamine is not a positive allosteric modulator of human alpha4beta2 or alpha7 nicotinic acetylcholine receptors. Br J Pharmacol 175:2911–2925. https://doi.org/10.1111/bph.14329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Giunta B, Ehrhart J, Townsend K et al (2004) Galantamine and nicotine have a synergistic effect on inhibition of microglial activation induced by HIV-1 gp120. Brain Res Bull 64:165–170. https://doi.org/10.1016/j.brainresbull.2004.06.008

    Article  CAS  PubMed  Google Scholar 

  94. Takata K, Kitamura Y, Saeki M et al (2010) Galantamine-induced amyloid-{beta} clearance mediated via stimulation of microglial nicotinic acetylcholine receptors. J Biol Chem 285:40180–40191. https://doi.org/10.1074/jbc.M110.142356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kume T, Sugimoto M, Takada Y et al (2005) Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat cortical neurons. Eur J Pharmacol 527:77–85. https://doi.org/10.1016/j.ejphar.2005.10.028

    Article  CAS  PubMed  Google Scholar 

  96. Takada-Takatori Y, Kume T, Ohgi Y et al (2008) Mechanisms of alpha7-nicotinic receptor up-regulation and sensitization to donepezil induced by chronic donepezil treatment. Eur J Pharmacol 590:150–156. https://doi.org/10.1016/j.ejphar.2008.06.027

    Article  CAS  PubMed  Google Scholar 

  97. Hwang J, Hwang H, Lee HW et al (2010) Microglia signaling as a target of donepezil. Neuropharmacology 58:1122–1129. https://doi.org/10.1016/j.neuropharm.2010.02.003

    Article  CAS  PubMed  Google Scholar 

  98. Arikawa M, Kakinuma Y, Noguchi T et al (2016) Donepezil, an acetylcholinesterase inhibitor, attenuates LPS-induced inflammatory response in murine macrophage cell line RAW 264.7 through inhibition of nuclear factor kappa B translocation. Eur J Pharmacol 789:17–26. https://doi.org/10.1016/j.ejphar.2016.06.053

    Article  CAS  PubMed  Google Scholar 

  99. Wang H, Liao H, Ochani M et al (2004) Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 10:1216–1221. https://doi.org/10.1038/nm1124

    Article  CAS  PubMed  Google Scholar 

  100. Cacace R, Sleegers K, Van Broeckhoven C (2016) Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement 12:733–748. https://doi.org/10.1016/j.jalz.2016.01.012

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Annalisa Maroli for her help in the artworks.

Funding

This work was supported by the National Research Council of Italy (CNR), Research Project Aging: molecular and technological innovations for improving the health of the elderly population (Prot. MIUR 2867 25.11.2011).

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Authors and Affiliations

  1. CNR-Neuroscience Institute, Via Vanvitelli 32, 20129, Milan, Italy

    Roberta Benfante & Diego Fornasari

  2. Dept. Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Via Vanvitelli 32, 20129, Milan, Italy

    Roberta Benfante, Simona Di Lascio, Silvia Cardani & Diego Fornasari

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  1. Roberta Benfante
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  2. Simona Di Lascio
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Correspondence to Roberta Benfante.

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Benfante, R., Di Lascio, S., Cardani, S. et al. Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: a new therapeutic perspective in aging-related disorders. Aging Clin Exp Res 33, 823–834 (2021). https://doi.org/10.1007/s40520-019-01359-4

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