Advertisement

S 24795 Limits β-Amyloid–α7 Nicotinic Receptor Interaction and Reduces Alzheimer's Disease-Like Pathologies

Published:November 23, 2009DOI:https://doi.org/10.1016/j.biopsych.2009.09.031

      Background

      Beta-amyloid (Aβ) enables Alzheimer's disease (AD) plaque and neurofibrillary pathogenesis. Soluble Aβ promotes intraneuronal Aβ aggregates and τ phosphorylation by interacting with α7 nicotinic receptors (α7nAChRs). The current study assessed whether the novel α7nAChR partial agonist 2-(2-(4-bromophenyl)-2-oxoethyl)-1-methyl pyridinium (S 24795) could reduce AD-like pathologies by interfering with Aβ–α7nAChR interaction.

      Methods

      We compared the in vitro effect of S 24795, memantine, galantamine, and Aβ12-28 on Aβ42–α7nAChR interaction in rat hippocampal synaptosomes. We further evaluated the effect of S 24795 on Aβ42-induced τ phosphorylation with rat hippocampal synaptosomes in vitro. Effects of S 24795 on Aβ42 immunostaining, Aβ42–α7nAChR interaction, and/or Aβ42-mediated reduction of calcium (Ca2+) influx through α7nAChR and N-methyl-d-aspartate receptor (NMDAR) were assessed in Aβ42-incubated organotypic brain slices and intracerebroventricularly (ICV) Aβ42-injected mouse brain.

      Results

      Preincubation with S 24795 in vitro reduces Aβ42–α7nAChR interaction and Aβ42-induced τ phosphorylation. In organotypic brain slice cultures and in an ICV Aβ42 injection in vivo model, S 24795 reduces Aβ42–α7nAChR association and Aβ42 immunostaining. S 24795 also normalizes Ca2+ fluxes through both α7nAChR and NMDAR channels in Aβ42-infused mouse brains and Aβ42-exposed organotypic cortical slices. Unlike S 24795 and Aβ12-28, galantamine or memantine minimally affect Aβ42–α7nAChR coupling and Aβ42-mediated reduction of α7nAChR- and NMDAR-mediated Ca2+ influx.

      Interpretation

      Drugs like S 24795 that disrupt Aβ42–α7nAChR interaction might alleviate Aβ42-mediated synaptic dysfunction and block AD-like pathologies.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Selkoe D.J.
        Toward a comprehensive theory for Alzheimer's disease.
        Ann N Y Acad Sci. 2000; 924: 17-25
        • Naslund J.
        • Haroutunian V.
        • Mohs R.
        • Davis K.L.
        • Davies P.
        • Greengard P.
        • et al.
        Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline.
        JAMA. 2000; 283: 1571-1577
        • Wang H.Y.
        • Lee D.H.S.
        • D'Andrea M.R.
        • Peterson P.A.
        • Shank R.P.
        • Reitz A.B.
        β-amyloid1-42 binds to α7 nicotinic acetylcholine receptor with high affinity: Implications for Alzheimer's disease pathology.
        J Biol Chem. 2000; 275: 5626-5632
        • Wang H.Y.
        • Lee D.H.S.
        • Davis C.B.
        • Shank R.P.
        Amyloid peptide Aβ1-42 binds selectively and with pico-molar affinity to α7 nicotinic acetylcholine receptors.
        J Neurochem. 2000; 75: 1155-1161
        • Nagele R.G.
        • D'Andrea M.R.
        • Anderson W.J.
        • Wang H.Y.
        Intracellular accumulation of beta-amyloid (1–42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer's disease.
        Neuroscience. 2002; 110: 199-211
        • Wang H.Y.
        • Li W.
        • Benedetti N.
        • Lee D.H.S.
        α7 nicotinic acetylcholine receptors α7 nicotinic acetylcholine receptors mediate β−amyloid peptides-induced tau protein phosphorylation.
        J Biol Chem. 2003; 278: 31547-31553
        • Pettit D.L.
        • Shao Z.
        • Yakel J.L.
        β-amyloid1-42 peptide directly modulates nicotinic receptors in the rat hippocampal slice.
        J Neurosci. 2001; 21: RC120-RC125
        • Liu Q.S.
        • Kawai H.
        • Berg D.K.
        Beta-amyloid peptide blocks the response of alpha7-containing nicotinic receptors on hippocampal neurons.
        Proc Natl Acad Sci U S A. 2001; 48: 4734-4739
        • Lee D.H.S.
        • Wang H.Y.
        Differential physiologic responses of alpha7 nicotinic acetylcholine receptors to beta-amyloid1-40 and beta-amyloid1-42.
        J Neurobiol. 2003; 55: 25-30
        • Cincotta S.L.
        • Yorek M.S.
        • Moschak T.M.
        • Lewis S.R.
        • Rodefer J.S.
        Selective nicotinic acetylcholine receptor agonists: Potential therapies for neuropsychiatric disorders with cognitive dysfunction.
        Curr Opin Investig Drugs. 2008; 9: 47-59
        • Lopez-Hernandez G.
        • Placzek A.N.
        • Thinschimdt J.S.
        • Lestage P.
        • Trocme-Thibierge C.
        • Morain P.
        • et al.
        Partial agonist and neuromodulatory activity of S 24795 for alpha7 nAChR responses of hippocampal interneurons.
        Neuropharmacology. 2007; 53: 134-144
        • Lagostena L.
        • Trocme-Thibierge C.
        • Morain P.
        • Cherubini E.
        The partial α7 nicotine acetylcholine receptor agonist S 24795 enhances long-term potentiation at CA3-CA1 synapses in the adult mouse hippocampus.
        Neuropharmacology. 2008; 54: 676-685
        • Beracochea D.
        • Boucard A.
        • Trocme-Thibierge C.
        • Morain P.
        Improvement of contextual memory by S 24795 in aged mice: Comparison with memantine.
        Psychopharmacology. 2008; 196: 555-564
        • Marighetto A.
        • Valerio S.
        • Desmedt A.
        • Philippin J.P.
        • Trocmé-Thibierge C.
        • Morain P.
        Comparative effects of the α7 nicotinic partial agonist, S 24795 and cholinesterase inhibitor donepezil against aging-related deficits in declarative and working memory in mice.
        Psychopharmacology. 2008; 197: 499-508
        • Stoppini I.
        • Bushs P.A.
        • Mulker D.
        A simple method for organotypic cultures of nervous tissue.
        J Neurosci Methods. 1991; 37: 173-182
        • Adamchik Y.
        • Frantseva M.V.
        • Weisspapir M.
        • Carlen P.L.
        • Perez-Velazquez J.L.
        Methods to induce primary and secondary traumatic damage in organotypic hippocampal slices cultures.
        Brain Res Protoc. 2000; 5: 153-158
        • Flood J.F.
        • Morley J.E.
        • Roberts E.
        Amnestic effects in mice of four synthetic peptides homologous to amyloid beta protein from patients with Alzheimer's disease.
        Proc Natl Acad Sci U S A. 1991; 88: 3363-3366
        • Yamada Y.
        • Nabeshima T.
        Animal models of Alzheimer's disease and evaluation of anti-dementia drugs.
        Pharmacol Ther. 2000; 88: 93-113
        • D'Andrea M.R.
        • Nagele R.G.
        • Wang H.Y.
        • Peterson P.A.
        • Lee D.H.S.
        Evidence that neurons accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease.
        Histopathology. 2001; 38: 120-134
        • Battaglia F.
        • Wang H.Y.
        • Ghilardi M.F.
        • Gashi E.
        • Quartarone A.
        • Friedman E.
        • et al.
        Cortical plasticity in Alzheimer's disease in humans and rodents.
        Biol Psychiatry. 2007; 62: 1405-1412
        • LaFerla F.M.
        • Tinkle B.T.
        • Bieberich C.J.
        • Haudenschild C.C.
        • Jay G.
        The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice.
        Nat Genet. 1995; 1: 21-30
        • LaFerla F.M.
        • Troncoso J.C.
        • Strickland D.K.
        • Kawas C.H.
        • Jay G.
        Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Abeta stabilization.
        J Clin Invest. 1997; 100: 310-320
        • Gouras G.K.
        • Tsai J.
        • Naslund J.
        • Vicent B.
        • Edgar M.
        • Checler F.
        • et al.
        Intraneuronal Abeta42 accumulation in human brain.
        Am J Pathol. 2000; 156: 15-20
        • Oddo S.
        • Caccamo A.
        • Shepherd J.D.
        • Murphy M.P.
        • Golde T.E.
        • Kayed R.
        • et al.
        Triple- transgenic model of Alzheimer's disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction.
        Neuron. 2003; 39: 409-421
        • Takahashi R.H.
        • Milner T.A.
        • Li F.
        • Nam E.E.
        • Edgar M.A.
        • Yamaguchi H.
        • et al.
        Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.
        Am J Pathol. 2002; 161: 1869-1879
        • Perry G.
        • Cras P.
        • Siedlak S.L.
        • Tabaton M.
        • Kawai M.
        Beta protein immunoreactivity is found in the majority of neurofibrillary tangles of Alzheimer's disease.
        Am J Pathol. 1992; 140: 283-290
        • Zhang Y.
        • McLaughlin R.
        • Goodyer C.
        • LeBlanc A.
        Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons.
        J Cell Biol. 2000; 156: 519-529
        • Tseng B.P.
        • Kitazawa M.
        • LaFerla F.M.
        Amyloid beta-peptide: The inside story.
        Curr Alzheimer Res. 2004; 1: 231-239
        • Dineley K.T.
        • Westereman M.
        • Bui D.
        • Bell K.
        • Ashe K.H.
        • Sweatt J.D.
        Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease.
        J Neurosci. 2001; 21: 4125-4133
        • Liu Q.
        • Huang Y.
        • Xue F.
        • Simard A.
        • DeChon J.
        • Li G.
        • et al.
        A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides.
        J Neurosci. 2009; 29: 918-929
        • Snyder E.M.
        • Nong Y.
        • Almeida C.G.
        • Paul S.
        • Moran T.
        • Choi E.Y.
        • et al.
        Regulation of NMDA receptor trafficking by amyloid-beta.
        Nat Neurosci. 2005; 8: 1051-1058
        • Mansvelder H.D.
        • McGehee D.S.
        Long-term potentiation of excitatory inputs to brain reward areas by nicotine.
        Neuron. 2000; 27: 349-357
        • Fujii S.
        • Jia Y.
        • Yang A.
        • Sumikawa K.
        Nicotine reverses GABAergic inhibition of long-term potentiation induction in the hippocampal CA1 region.
        Brain Res. 2000; 863: 259-265
        • Matsuyama S.
        • Matsumoto A.
        • Enomoto T.
        • Nishizaki T.
        Activation of nicotinic acetylcholine receptors induces long-term potentiation in vivo in the intact mouse dentate gyrus.
        Eur J Neurosci. 2000; 12: 3741-3747
        • Itoh A.
        • Akaike T.
        • Sokabe M.
        • Nitta A.
        • Iida R.
        • Olariu A.
        • et al.
        Impairments of long-term potentiation in hippocampal slices of beta-amyloid-infused rats.
        Eur J Pharmacol. 1999; 382: 167-175
        • Chen L.
        • Yamada K.
        • Nabeshima T.
        • Sokabe M.
        alpha7 nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal LTP induction in beta-amyloid infused rats.
        Neuropharmacology. 2006; 50: 254-268
        • Levin E.D.
        • Bettegowda C.
        • Blosser J.
        • Gordon J.
        AR-R17779, an alpha7 nicotinic agonist, improves learning and memory in rats.
        Behav Pharmacol. 1999; 10: 675-680
        • Woodruff-Pak D.S.
        • Green J.T.
        • Coleman-Valencia C.
        • Pak J.T.
        A nicotinic cholinergic agonist (GTS-21) and eyebrink classical conditioning: Acquisition, retention, relearning in older rabbits.
        Exp Aging Rev. 2000; 26: 323-336
        • Dziewczapolski G.
        • Glogowski C.M.
        • Masliah E.
        • Heinemann S.F.
        Deletion of the α7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease.
        J Neurosci. 2009; 29: 8805-8815
        • Wang H.Y.
        • Stucky A.
        • Liu J.J.
        • Shen C.
        • Trocmé-Thibierge C.
        • Morain P.
        Dissociating β-amyloid from α7 nicotinic receptor by a novel therapeutic agent, S 24795 normalizes α7 nicotinic acetylcholine and NMDA receptor function in Alzheimer's disease brain.
        J Neurosci. 2009; 29: 10961-10973
        • Bullock R.
        • Dengiz A.
        Cognitive performance in patients with Alzheimer's disease receiving cholinesterase inhibitors for up to 5 years.
        Int J Clin Pract. 2006; 59: 817-822
        • Tariot P.N.
        • Farlow M.R.
        • Grossberg G.T.
        • Graham S.M.
        • McDonald S.
        • Gergel I.for the Memantine Study group
        Memantine treatment in patients with moderate to severe Alzheimer's disease already receiving donepezil.
        JAMA. 2004; 291: 317-324
        • Parsons C.G.
        • Danysz W.
        • Quack G.
        Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data.
        Neuropharmacology. 1999; 38: 735-767
        • Aracava Y.
        • Pereira E.F.
        • Maelicke A.
        • Albuquerque E.X.
        Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons.
        J Pharmacol Exp Ther. 2005; 312: 1195-1205
        • Capsoni S.
        • Giannotta S.
        • Cattaneo A.
        Nerve growth factor and galantamine ameliorate early sign of neurodegeneration in anti-nerve growth factor mice.
        Proc Natl Acad Sci U S A. 2002; 99: 12432-12437
        • Takada Y.
        • Yonezawa A.
        • Kume T.
        • Katsuki H.
        • Kaneko S.
        • Sugimoto H.
        • et al.
        Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons.
        J Pharmacol Exp Ther. 2003; 306: 772-777
        • Arias E.
        • Ales E.
        • Gabilan N.
        • Cano-Abad M.
        • Villarroya M.
        • Garcia A.
        • et al.
        Galantamine prevents apoptosis induced by β-amyloid and thiapsigargin: Involvement of nicotinic acetylcholine receptors.
        Neuropharmacology. 2004; 46: 103-114
        • Yamada K.
        • Takayanagi M.
        • Kamei H.
        • Nagai T.
        • Dohniwa M.
        • Kobayashi K.
        • et al.
        Effects of memantine and donepezil on amyloid β-induced memory impairment in a delayed-matching to position task in rats.
        Behav Brain Res. 2005; 162: 191-199