β-Amyloid Peptide Activates α7 Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes

Abstract

The α7 nicotinic acetylcholine receptor is highly expressed in hippocampus and in cholinergic projection neurons from the basal forebrain, structures that are particularly vulnerable to the ravages of Alzheimer's disease. Previous work suggests that β-amyloid peptide can interact with α7 nicotinic acetylcholine receptors, although the nature of this interaction has not been well characterized. To test whether β-amyloid peptide can activate α7 nicotinic acetylcholine receptors, we expressed these receptors inXenopus oocytes and performed two-electrode voltage clamp recordings, characterizing the response to β-amyloid peptide 1–42 applied at concentrations ranging from 1 pm to 100 nm. In α7-expressing oocytes, β-amyloid peptide 1–42 elicits inward currents at low concentrations (1–100 pm), whereas at higher concentrations (nm), less effective receptor activation is observed, indicative of receptor desensitization. Preincubation with the α7-selective agents, the antagonist methyllycaconatine, and the agonist 4-OH-GTS-21 blocked β-amyloid peptide-induced receptor activation. β-amyloid peptide 1–42 at low concentrations was able to activate the L250T mutant α7 receptor. The endogenous Ca2+-activated chloride current inXenopus oocytes is recruited upon receptor activation since replacing Ca2+ with Ba2+ in the recording solution reduced current amplitude. Thus, when β-amyloid peptide activation of α7 receptors occurs, these currents are comprised, at least in part, of Ca2+. The α7 nicotinic acetylcholine receptor is highly expressed in hippocampus and in cholinergic projection neurons from the basal forebrain, structures that are particularly vulnerable to the ravages of Alzheimer's disease. Previous work suggests that β-amyloid peptide can interact with α7 nicotinic acetylcholine receptors, although the nature of this interaction has not been well characterized. To test whether β-amyloid peptide can activate α7 nicotinic acetylcholine receptors, we expressed these receptors inXenopus oocytes and performed two-electrode voltage clamp recordings, characterizing the response to β-amyloid peptide 1–42 applied at concentrations ranging from 1 pm to 100 nm. In α7-expressing oocytes, β-amyloid peptide 1–42 elicits inward currents at low concentrations (1–100 pm), whereas at higher concentrations (nm), less effective receptor activation is observed, indicative of receptor desensitization. Preincubation with the α7-selective agents, the antagonist methyllycaconatine, and the agonist 4-OH-GTS-21 blocked β-amyloid peptide-induced receptor activation. β-amyloid peptide 1–42 at low concentrations was able to activate the L250T mutant α7 receptor. The endogenous Ca2+-activated chloride current inXenopus oocytes is recruited upon receptor activation since replacing Ca2+ with Ba2+ in the recording solution reduced current amplitude. Thus, when β-amyloid peptide activation of α7 receptors occurs, these currents are comprised, at least in part, of Ca2+. Alzheimer disease β-amyloid peptide Aβ-(X−40) Aβ-(X−42) nicotinic acetylcholine receptor extracellular signal-regulated kinase mitogen-activated protein kinase methyllycaconatine 3-(4-hydroxy, 2-methoxybenzylidene)anabaseine 4-OH-GTS-21 Alzheimer's Disease (AD)1 is the most common of the senile dementias, the prevalence of which is increasing rapidly with a projected 14 million affected worldwide by 2025. Early on, AD presents clinically as impaired memory formation, yet despite intensive study, the mechanisms underlying AD-related memory dysfunction remain mysterious. Familial AD is associated with several risk factors, the best correlated being age and the inheritance of specific genes (mutations or allele type) that predominantly result in increased β-amyloid peptide (Aβ) levels (1Kuo Y.M. Emmerling M.R. Vigo-Pelfrey C. Kasunic T.C. Kirkpatrick J.B. Murdoch G.H. Ball M.J. Roher A.E. J. Biol. Chem. 1996; 271: 4077-4081Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 2Selkoe D.J. Trends Cell Biol. 1998; 8: 447-453Abstract Full Text Full Text PDF PubMed Scopus (805) Google Scholar, 33Price D.L. Tanzi R. Borchelt D.R. Sisodia S.S. Annu. Rev. Genet. 1998; 32: 461-493Crossref PubMed Scopus (357) Google Scholar). Although these peptides are present in the brains and cerebrospinal fluid of normal subjects at the picomolar level, substantial evidence indicates that elevated Aβ is a culprit in the cognitive decline of AD (1Kuo Y.M. Emmerling M.R. Vigo-Pelfrey C. Kasunic T.C. Kirkpatrick J.B. Murdoch G.H. Ball M.J. Roher A.E. J. Biol. Chem. 1996; 271: 4077-4081Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar). Aβ is generated from the amyloid precursor protein through endoproteolytic cleavage by β- and γ-secretases (2Selkoe D.J. Trends Cell Biol. 1998; 8: 447-453Abstract Full Text Full Text PDF PubMed Scopus (805) Google Scholar). In normal individuals, Aβ-(X−40) (Aβ40) comprises the majority of the Aβ population; a far smaller fraction is made up of Aβ42 (1Kuo Y.M. Emmerling M.R. Vigo-Pelfrey C. Kasunic T.C. Kirkpatrick J.B. Murdoch G.H. Ball M.J. Roher A.E. J. Biol. Chem. 1996; 271: 4077-4081Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar). Aβ42 is highly fibrillogenic and exhibits trophic and toxic effects on neurons (3Lambert M.P. Barlow A.K. Chromy B.A. Edwards C. Freed R. Liosatos M. Morgan T.E. Rozovsky I. Trommer B. Viola K.L. Wals P. Zhang C. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6448-6453Crossref PubMed Scopus (3129) Google Scholar, 4Hartley D.M. Walsh D.M., Ye, C.P. Diehl T. Vasquez S. Vassilev P.M. Teplow D.B. Selkoe D.J. J. Neurosci. 1999; 19: 8876-8884Crossref PubMed Google Scholar, 5Dodart J.C. Mathis C. Ungerer A. Rev. Neurosci. 2000; 11: 75-93Crossref PubMed Scopus (50) Google Scholar). The hippocampus is a locus for the earliest detected cognitive dysfunction in AD: impairment in the encoding of new episodic memories is typical of the earliest stages of AD, and the loss of episodic memory in AD is linked to medial temporal pathology inclusive of the hippocampus (6Butters N. Granholm E. Salmon D.P. Grant I. Wolfe J. J. Clin. Exp. Neuropsychol. 1987; 9: 479-497Crossref PubMed Scopus (477) Google Scholar, 7Fox N.C. Warrington E.K. Freeborough P.A. Hartikainen P. Kennedy A.M. Stevens J.M. Rossor M.N. Brain. 1996; 119: 2001-2007Crossref PubMed Scopus (522) Google Scholar, 8Fox N.C. Warrington E.K. Stevens J.M. Rossor M.N. Ann. N. Y. Acad. Sci. 1996; 777: 226-232Crossref PubMed Scopus (67) Google Scholar). Despite intensive study, the mechanism by which elevated Aβ leads to AD-related hippocampal dysfunction remains mysterious, not to mention the lack of an understanding of the normal physiologic role for Aβ in synaptic function and signal transduction. As yet, a receptor for Aβ that is capable of influencing synaptic plasticity in the hippocampus remains unidentified. Cholinergic connections between the hippocampus and cortical structures within the temporal lobe and the cortical cholinergic system that originates within the basal forebrain are selectively vulnerable in the course of AD (9Bowen D.M. Smith C.B. White P. Davison A.N. Brain. 1976; 99: 459-496Crossref PubMed Scopus (1028) Google Scholar, 10Davies P. Maloney A.J. Lancet. 1976; 2: 1403Abstract PubMed Scopus (2827) Google Scholar, 11Perry E.K. Perry R.H. Blessed G. Tomlinson B.E. Lancet. 1977; 1: 189Abstract PubMed Scopus (711) Google Scholar). The loss of proper functioning of these neuronal populations is thought to underlie the loss of memory in AD patients (12Bartus R.T. Dean 3rd, R.L. Beer B. Lippa A.S. Science. 1982; 217: 408-414Crossref PubMed Scopus (4805) Google Scholar, 13Bartus R.T. Exp. Neurol. 2000; 163: 495-529Crossref PubMed Scopus (692) Google Scholar). The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed on neurons of hippocampus and cholinergic projection neurons from the basal forebrain. A number of recent studies have convincingly demonstrated an interaction between the α7 nAChR and Aβ in vitro and on neurons. For instance, it has been shown that Aβ42 co-immunoprecipitates with the α7 nAChR in samples from postmortem AD hippocampus and that α7 nAChR antagonists compete for Aβ42 binding to heterologously expressed α7 nAChRs (14Wang H.Y. Lee D.H. D'Andrea M.R. Peterson P.A. Shank R.P. Reitz A.B. J. Biol. Chem. 2000; 275: 5626-5632Abstract Full Text Full Text PDF PubMed Scopus (729) Google Scholar). Furthermore, preincubation with Aβ42 antagonizes the activation of α7 nAChR-like currents in hippocampal neurons, and Aβ42, acting through α7 nAChRs, can elicit extracellular signal-regulated kinase (ERK) MAPK activation in hippocampal cultures (15Pettit D.L. Shao Z. Yakel J.L. J. Neurosci. 2001; 21: RC120Crossref PubMed Google Scholar, 16Liu Q. Kawai H. Berg D.K. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 4734-4739Crossref PubMed Scopus (293) Google Scholar). This last observation is likely triggered by Ca2+ influx; α7 nAChRs are highly permeable to this pluripotent second messenger (17Seguela P. Wadiche J. Dineley-Miller K. Dani J.A. Patrick J.W. J. Neurosci. 1993; 13: 596-604Crossref PubMed Google Scholar). We tested the hypothesis that Aβ could directly activate the α7 nAChR by expressing these receptors in Xenopus oocytes and performing two-electrode voltage clamp recordings following perfusion with pm to nm concentrations of non-aggregate Aβ. Both Aβ40 and Aβ42 were capable of eliciting inward currents from α7 nAChR-expressing oocytes; however, the current amplitudes resulting from Aβ42 receptor activation were much larger than those generated by Aβ40. Inward currents elicited by Aβ42 were comprised of Ca2+, were blocked by the α7 nAChR-selective antagonist methyllycaconatine (MLA), and were cross-desensitized by the α7 nAChR-selective agent 4OH-GTS-21. We obtained evidence that low concentrations of Aβ42 are highly desensitizing; wash times up to 30 min were unsuccessful at allowing subsequent Aβ42 activation. Desensitization induced by low concentrations of Aβ42 did not have an observable effect on subsequent nicotine stimulation. However, prolonged exposure to a high concentration of Aβ42 led to cross-desensitization of nicotine responses, suggesting the existence of more than one Aβ42 binding site or an Aβ42-induced conformation that differentially interferes with nicotine activation of α7 nAChRs. Overall, we conclude that Aβ42 is a high affinity ligand for α7 nAChRs that is capable of gating Ca2+ flux through the channel. Xenopus leavis (Nasco) oocytes were harvested and prepared for injection as described (17Seguela P. Wadiche J. Dineley-Miller K. Dani J.A. Patrick J.W. J. Neurosci. 1993; 13: 596-604Crossref PubMed Google Scholar). Rat α7 nAChR cDNA or rat α7 nAChR cDNA containing the point mutation L250T, both contained in the cytomegalovirus were for α7 nAChR were obtained from the of oocytes were with of cDNA 1 following a were at in 1 and to currents were from oocytes were at a of in the recording with solution for solution in which was and peptides nicotine A. J. R.L. J. Exp. 1998; Google by of and the peptide rat 100 of Aβ were prepared to and to formation, as described M. K. J. Neurosci. 2001; 21: PubMed Google were in solution to voltage clamp was performed at an and voltage were with and from to were at with and and voltage clamp of less than 100 were was by were at a of and for and and was performed with amplitudes were by the from and as of nicotine response for in by We in the nicotine a of which could have been to the in α7 nAChR following the of agonist J.C. R.L. Google oocytes at least of nicotine by min at the of recording with the of those for with α7 nAChR cDNA were tested for by performing a test perfusion with 100 with L250T mutant α7 nAChR cDNA were tested for by performing a test perfusion with 1 or inward currents of at least 100 in response to nicotine were in work rat Aβ42 peptide that was prepared to and B. M. J. M. A. J. C. C. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We tested Aβ42 for in a the concentrations and the of the Aβ42 of solution with at or not shown PubMed Scopus Google The of low concentrations of Aβ42 to activate α7 nAChRs was tested by expressing these receptors in the Xenopus system and performing two-electrode voltage clamp for α7 nAChR as with a perfusion of 100 were for min with solution and to a perfusion with This concentration of Aβ42 led to inward currents that or in activation with nicotine was not to Aβ42-induced We receptor activation following Aβ42 perfusion on oocytes that not yet been to α7 nAChR Furthermore, we did not current when oocytes were to Aβ42 perfusion not We tested whether the far more of amyloid was capable of α7 nAChRs expressed by Xenopus pm Aβ40 generated inward currents from α7 nAChR-expressing However, the current amplitudes were much smaller than an concentration of the Aβ40 currents were less than of those generated with pm Aβ40 elicited which is of the 100 nicotine response not the peptide to α7 nAChR activation not that Aβ42, as well as is a and high affinity agonist for α7 nAChRs expressed in we whether we could α7 nAChR activation with of activation of α7 nAChRs with nicotine could by performing between In following a perfusion with pm Aβ42 that a current we were to a second Aβ42 response 1 This was the for wash times of up to 30 at this low concentration of Aβ42, loss of the Aβ response did not with the nicotine with 100 within 1 min of perfusion with the second of Aβ42 in a nicotine response that was from the nicotine test the activation of low concentrations of Aβ42 and of 100 nicotine on α7 nAChRs are Previous have demonstrated Aβ42 of α7 nAChRs expressed by neurons (15Pettit D.L. Shao Z. Yakel J.L. J. Neurosci. 2001; 21: RC120Crossref PubMed Google Scholar, 16Liu Q. Kawai H. Berg D.K. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 4734-4739Crossref PubMed Scopus (293) Google Scholar). studies high concentrations of Aβ42 and tested α7 nAChR following preincubation with the We to the nicotine response of α7 nAChRs expressed by oocytes with 100 A preincubation of nicotine and Aβ42 did not the receptor with 100 the of the receptors to subsequent 100 nicotine 1 are with the that 100 nm and 1 Aβ42 of neuronal α7 nAChR to agonist (15Pettit D.L. Shao Z. Yakel J.L. J. Neurosci. 2001; 21: RC120Crossref PubMed Google Scholar, 16Liu Q. Kawai H. Berg D.K. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 4734-4739Crossref PubMed Scopus (293) Google Scholar). We demonstrated that the Aβ42 effect could blocked by the α7 nAChR-selective a a from in which blocked both the nicotine and pm Aβ42 response from an expressing α7 nAChRs. of the nicotine response a with solution to a second of Aβ42 was not the following preincubation with the α7 nAChR-selective agent 4-OH-GTS-21 or 30 cross-desensitized the of Aβ42 to activate α7 nAChRs on oocytes to nicotine and to a perfusion with 4-OH-GTS-21 subsequent activation of α7 nAChRs with pm A with solution the Aβ42-induced 4-OH-GTS-21 cross-desensitized nicotine as well not The that a response to a second of Aβ42 was suggests that 4-OH-GTS-21 binding Aβ42 binding and that the binding that Aβ42 is a agonist for α7 nAChRs expressed in We the mutant L250T α7 nAChR to the currents generated by this receptor J.L. A. C. N. S. M. PubMed Scopus Google Scholar, A. J.L. N. C. S. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). a test of 1 nicotine and a wash with pm Aβ42 was for 30 which in a substantial inward current times current as is of the the L250T mutant of the α7 nAChR and is by the in the of the currents the Aβ42-induced the that Aβ is more effective at eliciting of the L250T mutant receptors than is α7 nAChRs, we were able to to pm Aβ42 from the L250T mutant receptor following a wash between Aβ was not the however, that Aβ was to the receptor. of pm Aβ42 Aβ perfusion 1 induced current of current were to less than of the current not these wash times Aβ42 perfusion led to nicotine from the nicotine test Thus, to α7 nAChRs, a low concentration of Aβ42 has a effect on L250T nAChRs that not with nicotine We tested a of Aβ42 concentrations on both and L250T α7 nAChRs expressed in Xenopus concentration response for concentrations of Aβ42 ranging from 100 to 100 nm shown in is the effect of high concentrations of Aβ42 on receptor Aβ42 at nm concentrations is to both the and the mutant α7 nAChR expressed in Xenopus In the 100 nm effect on α7 nAChRs is not from current with high concentrations of Aβ42 receptor the concentration response an for both and L250T α7 nAChRs. In as the Aβ42 concentration the number of oocytes that to to Aβ42 although for α7 nAChR In with increasing Aβ42 a larger of oocytes to nicotine to to Aβ42 current amplitudes resulting from Aβ42 concentrations applied to or L250T mutant α7 nAChRs expressed in nm 1 100 the type) for a concentration of Aβ42 is the and the number of oocytes from which the was in a new the type) for a concentration of Aβ42 is the and the number of oocytes from which the was We concentrations of Aβ40 for to activate the L250T α7 As was for α7 nAChRs, Aβ40 L250T receptors to a much than an concentration of current amplitudes for 1 and 100 nm Aβ40 to L250T α7 nAChRs expressed in indicates that Aβ40 is less than Aβ42 at receptor current amplitudes resulting from Aβ40 concentrations applied to or L250T mutant α7 nAChRs expressed in nm 100 the type) for a concentration of Aβ42 is the and the number of oocytes from which the was in a new the type) for a concentration of Aβ42 is the and the number of oocytes from which the was Xenopus oocytes a Ca2+-activated chloride that a inward current when α7 nAChRs are highly permeable to Ca2+ (17Seguela P. Wadiche J. Dineley-Miller K. Dani J.A. Patrick J.W. J. Neurosci. 1993; 13: 596-604Crossref PubMed Google that when expressed in receptor activation leads to activation of the endogenous Ca2+-activated chloride channel. of Ca2+ with Ba2+ in the solution generated currents the chloride current to the We tested the that Aβ42 activation of α7 nAChRs leads to Ca2+ by performing recordings of the L250T mutant α7 nAChR following agonist in the and of Ca2+ in the perfusion in the of Ca2+, L250T α7 nAChRs inward currents in response to both nicotine and In the of Ca2+, L250T α7 nAChRs have reduced nicotine and Aβ42 responses, yet the current amplitudes are In the nicotine and Aβ42 were and of those in Ca2+ solution currents induced by nicotine or Aβ42 are to by the Ca2+-activated chloride with both nicotine and Aβ42 activation of α7 and in the of Ca2+, flux through these We have demonstrated that rat Aβ42 peptide prepared in non-aggregate directly rat α7 nAChRs expressed This is a high affinity concentrations as low as 100 Aβ42 are capable of inward Aβ42 is by and cross-desensitized by both α7 nAChR-selective receptors, the of effective Aβ42 the of Aβ that in normal as well as in AD (1Kuo Y.M. Emmerling M.R. Vigo-Pelfrey C. Kasunic T.C. Kirkpatrick J.B. Murdoch G.H. Ball M.J. Roher A.E. J. Biol. Chem. 1996; 271: 4077-4081Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar). This suggests the of an nAChR interaction normal physiologic and we that Aβ an endogenous ligand for α7 nAChRs. Furthermore, that of the pathology elicited by Aβ in AD to activation of α7 nAChRs. In as the α7 nAChR is a highly permeable to Ca2+ (17Seguela P. Wadiche J. Dineley-Miller K. Dani J.A. Patrick J.W. J. Neurosci. 1993; 13: 596-604Crossref PubMed Google activation of α7 nAChRs in AD could to of Ca2+ and a mechanism for the cholinergic dysfunction that is a of AD (9Bowen D.M. Smith C.B. White P. Davison A.N. Brain. 1976; 99: 459-496Crossref PubMed Scopus (1028) Google Scholar, 10Davies P. Maloney A.J. Lancet. 1976; 2: 1403Abstract PubMed Scopus (2827) Google Scholar, 11Perry E.K. Perry R.H. Blessed G. Tomlinson B.E. Lancet. 1977; 1: 189Abstract PubMed Scopus (711) Google Scholar). The more of amyloid peptide in was able to activate α7 nAChRs. However, Aβ40 was less effective than an concentration of Aβ42 at the and L250T mutant α7 nAChRs. however, that and rat Aβ by the of Aβ40 to rat Aβ40 on rat α7 nAChRs. is a in the of Aβ peptides at α7 nAChRs is at this that as well as Aβ42, is capable of nAChRs in we have and that is with current is that and memory in AD in of the increased Aβ and activation of the MAPK in the hippocampus through α7 nAChRs M. K. J. Neurosci. 2001; 21: PubMed Google Scholar). In of we have demonstrated that of Aβ in an for AD K. P. S. C. Y. S. G. Science. 1996; PubMed Scopus Google leads to the of hippocampal α7 nAChR protein M. K. J. Neurosci. 2001; 21: PubMed Google Scholar). α7 nAChR in the hippocampus of is with the of a H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google a Neurosci. 1993; PubMed Scopus Google Scholar, Neurosci. PubMed Scopus Google Scholar). Furthermore, increased α7 nAChR protein levels are detected with of the of MAPK M. K. J. Neurosci. 2001; 21: PubMed Google Scholar). that MAPK is for α7 nAChR in hippocampus as a for the synaptic plasticity and and memory in that result from elevated Aβ J.C. J.M. Neurosci. 1998; 1: PubMed Scopus Google Scholar, S. A.N. J. Neurosci. 1999; 19: PubMed Google Scholar, J.C. J.M. R. 1999; PubMed Scopus Google Scholar). observation of of α7 nAChRs by low concentrations of Aβ42 prolonged of binding on α7 nAChRs. This interaction is with the hypothesis by H.Y. Lee D.H. C.B. Shank R.P. J. 2000; PubMed Scopus Google that α7 nAChRs or Aβ to the the conformation of Aβ in the is with α7 nAChRs the of Aβ levels of Aβ the binding of α7 nAChRs. L250T mutant α7 nAChRs were to of Aβ42 effects on receptors these mutant α7 receptors much current J.L. A. C. N. S. M. PubMed Scopus Google A. J.L. N. C. S. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). studies demonstrated a high affinity interaction of Aβ42 with the α7 with described J.L. A. C. N. S. M. PubMed Scopus Google Scholar, A. J.L. N. C. S. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google L250T receptors can by Aβ42 with between However, in the of Aβ42-induced receptor In a to the effects of low concentrations of Aβ on α7 nAChRs, nicotine from L250T receptors were when these receptors were to A of the L250T current is to activation of the endogenous Ca2+-activated chloride current in Xenopus the effects of Aβ42 on L250T with the receptor and that receptor activation leads to Ca2+ these we have shown that Aβ42 the MAPK through α7 nAChRs in hippocampal M. K. J. Neurosci. 2001; 21: PubMed Google Scholar). This activation extracellular Ca2+ and not Thus, it is that MAPK activation in hippocampus from Ca2+ directly through α7 nAChRs following of the L250T α7 nAChR current response to nicotine Aβ42 is the current nicotine and for this receptor perfusion J.L. A. C. N. S. M. PubMed Scopus Google Scholar, A. J.L. N. C. S. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google at concentrations of Aβ42 Aβ leads to more of L250T than 1 or This observation or We the that Aβ42 than acting as an since we not a current as a result of Furthermore, the to and rapidly activate α7 nAChRs with nicotine following of the Aβ42 response is with an channel. Thus, Aβ42 to L250T α7 nAChR in a than tested Aβ42 is highly to receptors in that high concentration or of Aβ42 the Aβ response in However, of the Aβ response with low concentrations of Aβ42 not with subsequent nicotine with Q. Kawai H. Berg D.K. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 4734-4739Crossref PubMed Scopus (293) Google did not of α7 nAChR to acetylcholine on hippocampal neurons following preincubation with Aβ42 at concentrations 1 nm. that the high affinity Aβ42 binding site and the nicotine binding site not or that the conformation induced by low concentrations of Aβ42 interferes with subsequent Aβ activation not with nicotine binding or receptor activation. We were able to nicotine activation of α7 nAChRs expressed in oocytes by preincubation with 100 nm are in with by (15Pettit D.L. Shao Z. Yakel J.L. J. Neurosci. 2001; 21: RC120Crossref PubMed Google and Q. Kawai H. Berg D.K. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 4734-4739Crossref PubMed Scopus (293) Google that preincubation with high concentrations of Aβ42 subsequent activation of expressed α7 nAChRs. that a affinity binding site for Aβ42 that with the agonist binding exposure to high concentrations of Aβ42 a in the receptor that is with subsequent activation with The of a affinity site for Aβ42 binding is by studies performed by H.Y. Lee D.H. C.B. Shank R.P. J. 2000; PubMed Scopus Google in which were detected with for Aβ42 binding to rat α7 nAChRs prepared from and hippocampus were and Furthermore, these binding are with observation that 1 α7 nAChRs. The work suggests that nAChR a role in the of We have demonstrated that Aβ peptide as a ligand for α7 nAChRs, and we evidence that the binding and activation of Aβ42 are from those of as low concentrations of Aβ42 activate the receptor and it to activation by the peptide not by higher concentrations receptor activation and it to The nature of Aβ42-induced receptor activation and indicates that the in on α7 nAChRs could to In however, that to the effects of Aβ on α7 nAChR function a for We and for with and We Patrick for the of this We are to for 4-OH-GTS-21 and for