The Butyrylcholinesterase K Variant Confers Structurally Derived Risks for Alzheimer Pathology♦

Abstract

The K variant of butyrylcholinesterase (BChE-K, 20% incidence) is a long debated risk factor for Alzheimer disease (AD). The A539T substitution in BChE-K is located at the C terminus, which is essential both for BChE tetramerization and for its capacity to attenuate β-amyloid (Aβ) fibril formation. Here, we report that BChE-K is inherently unstable as compared with the “usual” BChE (BChE-U), resulting in reduced hydrolytic activity and predicting prolonged acetylcholine maintenance and protection from AD. A synthetic peptide derived from the C terminus of BChE-K (BSP-K), which displayed impaired intermolecular interactions, was less potent in suppressing Aβ oligomerization than its BSP-U counterpart. Correspondingly, highly purified recombinant human rBChE-U monomers suppressed β-amyloid fibril formation less effectively than dimers, which also protected cultured neuroblastoma cells from Aβ neurotoxicity. Dual activity structurally derived changes due to the A539T substitution can thus account for both neuroprotective characteristics caused by sustained acetylcholine levels and elevated AD risk due to inefficient interference with amyloidogenic processes. The K variant of butyrylcholinesterase (BChE-K, 20% incidence) is a long debated risk factor for Alzheimer disease (AD). The A539T substitution in BChE-K is located at the C terminus, which is essential both for BChE tetramerization and for its capacity to attenuate β-amyloid (Aβ) fibril formation. Here, we report that BChE-K is inherently unstable as compared with the “usual” BChE (BChE-U), resulting in reduced hydrolytic activity and predicting prolonged acetylcholine maintenance and protection from AD. A synthetic peptide derived from the C terminus of BChE-K (BSP-K), which displayed impaired intermolecular interactions, was less potent in suppressing Aβ oligomerization than its BSP-U counterpart. Correspondingly, highly purified recombinant human rBChE-U monomers suppressed β-amyloid fibril formation less effectively than dimers, which also protected cultured neuroblastoma cells from Aβ neurotoxicity. Dual activity structurally derived changes due to the A539T substitution can thus account for both neuroprotective characteristics caused by sustained acetylcholine levels and elevated AD risk due to inefficient interference with amyloidogenic processes. Butyrylcholinesterase (BChE), 3The abbreviations used are: BChEbutyrylcholinesteraseBChE-KKalow variant of BChEBChE-Uusual BChErBChE-Urecombinant rBChE-UBSPBChE-derived synthetic peptideAChacetylcholineAChEacetylcholinesteraseAChE-Ssynaptic AChEATChacetylthiocholineADAlzheimer diseaseAββ-amyloidpolyPpoly-l-prolinebis-ANS4,4′-dianilino-1,1′-binaphthyl-5,5′-sulfonateTTRTransthyretinLDHlactate dehydrogenaseTEMtransmission electron microscopyThTthioflavin TTricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycineDMSOdimethyl sulfoxide. 3The abbreviations used are: BChEbutyrylcholinesteraseBChE-KKalow variant of BChEBChE-Uusual BChErBChE-Urecombinant rBChE-UBSPBChE-derived synthetic peptideAChacetylcholineAChEacetylcholinesteraseAChE-Ssynaptic AChEATChacetylthiocholineADAlzheimer diseaseAββ-amyloidpolyPpoly-l-prolinebis-ANS4,4′-dianilino-1,1′-binaphthyl-5,5′-sulfonateTTRTransthyretinLDHlactate dehydrogenaseTEMtransmission electron microscopyThTthioflavin TTricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycineDMSOdimethyl sulfoxide. the secondary acetylcholine (ACh)-hydrolyzing enzyme, is associated with the neurofibrillary tangles and amyloid plaques characteristic of Alzheimer disease (AD) (1Gómez-Ramos P. Morán M.A. Mol. Chem. Neuropathol. 1997; 30: 161-173Crossref PubMed Google Scholar), which suggests that it functions as a potential AD modulator. BChE activity increases in the AD brain (2Carson K.A. Geula C. Mesulam M.M. Brain Res. 1991; 540: 204-208Crossref PubMed Scopus (80) Google Scholar, 3Guillozet A.L. Smiley J.F. Mash D.C. Mesulam M.M. Ann. Neurol. 1997; 42: 909-918Crossref PubMed Scopus (271) Google Scholar, 4Perry E.K. Perry R.H. Blessed G. Tomlinson B.E. Neuropathol. Appl. Neurobiol. 1978; 4: 273-277Crossref PubMed Scopus (477) Google Scholar), where it co-localizes with β-amyloid (Aβ) fibrils (5Morán M.A. Mufson E.J. Gómez-Ramos P. Acta Neuropathol. 1993; 85: 362-369Crossref PubMed Scopus (167) Google Scholar, 6Wright C.I. Geula C. Mesulam M.M. Ann. Neurol. 1993; 34: 373-384Crossref PubMed Scopus (207) Google Scholar). Aβ is a 39–42-amino-acid amphiphilic peptide, derived from the transmembrane domain and extracellular region of the Aβ precursor protein (7Lansbury Jr., P.T. Biochemistry. 1992; 31: 6865-6870Crossref PubMed Scopus (149) Google Scholar). At high concentrations, Aβ acquires a β-sheet structure, becomes insoluble, and accumulates in neurotoxic oligomers and fibrils (8Lomakin A. Chung D.S. Benedek G.B. Kirschner D.A. Teplow D.B. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 1125-1129Crossref PubMed Scopus (732) Google Scholar) to become the main constituent of plaques in the brain of AD patients. Recent hypotheses attribute causal roles in AD to presenilin (9Shen J. Kelleher 3rd, R.J. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 403-409Crossref PubMed Scopus (372) Google Scholar), oxidative stress (10Praticó D. Ann. N.Y. Acad. Sci. 2008; 1147: 70-78Crossref PubMed Scopus (275) Google Scholar), metals (11Bush A.I. Tanzi R.E. Neurotherapeutics. 2008; 5: 421-432Crossref PubMed Scopus (483) Google Scholar), double hit origin (12Zhu X. Raina A.K. Perry G. Smith M.A. Lancet Neurol. 2004; 3: 219-226Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar), or mitochondrial damage (13Mancuso M. Coppedè F. Murri L. Siciliano G. Antioxid. Redox Signal. 2007; 9: 1631-1646Crossref PubMed Scopus (48) Google Scholar). The alternative theories state that Aβ represents a bystander or even a protector rather than the causative factor of disease and that Aβ amyloidogenesis is secondary to other pathogenic events (14Lee H.G. Casadesus G. Zhu X. Takeda A. Perry G. Smith M.A. Ann. N.Y. Acad. Sci. 2004; 1019: 1-4Crossref PubMed Scopus (141) Google Scholar). Nevertheless, a wealth of evidence demonstrates a pivotal role for Aβ in the pathogenesis of AD, yielding the amyloid cascade hypothesis (15Hardy J. Selkoe D.J. Science. 2002; 297: 353-356Crossref PubMed Scopus (10962) Google Scholar). According to this hypothesis, the pathological accumulation of Aβ in the brain leads to oxidative stress, neuronal destruction, and finally, the clinical syndrome of AD. It is within this context that we have studied the interactions of the Kalow variant (BChE-K) with Aβ. butyrylcholinesterase Kalow variant of BChE usual BChE recombinant rBChE-U BChE-derived synthetic peptide acetylcholine acetylcholinesterase synaptic AChE acetylthiocholine Alzheimer disease β-amyloid poly-l-proline 4,4′-dianilino-1,1′-binaphthyl-5,5′-sulfonate Transthyretin lactate dehydrogenase transmission electron microscopy thioflavin T N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine dimethyl sulfoxide. butyrylcholinesterase Kalow variant of BChE usual BChE recombinant rBChE-U BChE-derived synthetic peptide acetylcholine acetylcholinesterase synaptic AChE acetylthiocholine Alzheimer disease β-amyloid poly-l-proline 4,4′-dianilino-1,1′-binaphthyl-5,5′-sulfonate Transthyretin lactate dehydrogenase transmission electron microscopy thioflavin T N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine dimethyl sulfoxide. The C terminus of BChE functions as a tetramerization domain (16Altamirano C.V. Lockridge O. Chem. Biol. Interact. 1999; 119–120: 53-60Crossref PubMed Scopus (31) Google Scholar, 17Blong R.M. Bedows E. Lockridge O. Biochem. J. 1997; 327: 747-757Crossref PubMed Scopus (77) Google Scholar) and is responsible for its quaternary organization. Four BChE monomers are held together by the aromatic interactions of seven highly conserved aromatic residues, termed the tryptophan amphiphilic tetramerization domain (WAT) (16Altamirano C.V. Lockridge O. Chem. Biol. Interact. 1999; 119–120: 53-60Crossref PubMed Scopus (31) Google Scholar, 17Blong R.M. Bedows E. Lockridge O. Biochem. J. 1997; 327: 747-757Crossref PubMed Scopus (77) Google Scholar). The WAT domain interacts with proline-rich attachment domains, either via proline-rich membrane anchor in brain neurons (18Perrier A.L. Massoulié J. Krejci E. Neuron. 2002; 33: 275-285Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar) or, in neuromuscular junctions, with cholinesterase-associated collagen Q (19Bon S. Ayon A. Leroy J. Massoulié J. Neurochem. Res. 2003; 28: 523-535Crossref PubMed Scopus (31) Google Scholar). In the serum, BChE tetramerization is supported by an analogous 17-mer proline-rich peptide derived from lamellipodin (20Li H. Schopfer L.M. Masson P. Lockridge O. Biochem. J. 2008; 411: 425-432Crossref PubMed Scopus (84) Google Scholar). Analyzing the quaternary organization of cholinesterases is a complicated task. To date, all biologically relevant crystal structures of cholinesterases have been truncated forms that lack the C terminus of the protein (21Nicolet Y. Lockridge O. Masson P. Fontecilla-Camps J.C. Nachon F. J. Biol. Chem. 2003; 278: 41141-41147Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar), apart from a more recent study of full-length BChE that yielded crystal packing, which did not allow C-terminal interactions among subunits and lacked electron densities in the C terminus region, indicating structural disorder Protein Data Bank (PDB) code 1VZJ (22Ngamelue M.N. Homma K. Lockridge O. Asojo O.A. Acta Crystallogr. F Struct. Biol. Cryst. Commun. 2007; 63: 723-727Crossref PubMed Scopus (55) Google Scholar). Of note, the crystal structure of the homologous C terminus of tetrameric synaptic acetylcholinesterase (AChE-S) could only be determined based on synthetic peptides derived from the sequence of the AChE-S tail and stabilized with a proline-rich attachment domain (23Dvir H. Harel M. Bon S. Liu W.Q. Vidal M. Garbay C. Sussman J.L. Massoulié J. Silman I. EMBO J. 2004; 23: 4394-4405Crossref PubMed Scopus (92) Google Scholar). In addition to the “usual” (BChE-U) form, BChE has nearly 40 genomic variants. The most common is BChE-K, with allelic frequencies of 0.13–0.21. BChE-K includes a single nucleotide polymorphism at position 1699 (single nucleotide polymorphism data base (dbSNP) ID: rs1803274; alleles, A/G). This leads to an alanine-to-threonine substitution at position 539, 36 residues upstream to the C terminus of BChE (24Bartels C.F. Jensen F.S. Lockridge O. van der Spek A.F. Rubinstein H.M. Lubrano T. La Du B.N. Am. J. Hum. Genet. 1992; 50: 1086-1103PubMed Google Scholar), within the tetramerization domain that we previously found to attenuate amyloid fibril formation (25Diamant S. Podoly E. Friedler A. Ligumsky H. Livnah O. Soreq H. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 8628-8633Crossref PubMed Scopus (147) Google Scholar). Ample evidence supports the importance of alanine-to-threonine substitutions and their relevance to amyloidogenic processes, protein stability, and quaternary organization (supplemental Table ST1). Point mutations at the dimer interface of light chain immunoglobulins decrease their stability so that the A34T polymorphism in this protein leads to systemic amyloidosis (26Baden E.M. Owen B.A. Peterson F.C. Volkman B.F. Ramirez-Alvarado M. Thompson J.R. J. Biol. Chem. 2008; 283: 15853-15860Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). An A25T mutant of the tetrameric human protein Transthyretin (TTR), associated with central nervous system amyloidosis, is prone to aggregation and exhibits drastically reduced tertiary and quaternary structural stabilities (27Hurshman Babbes A.R. Powers E.T. Kelly J.W. Biochemistry. 2008; 47: 6969-6984Crossref PubMed Scopus (103) Google Scholar). The thermodynamic stability profile of the A25T TTR mutant shows that both monomers and tetramers of this variant are highly destabilized. In addition, A25T TTR tetramers dissociate very rapidly (about 1200-fold faster than the dissociation of wild-type TTR), reflecting a high degree of kinetic destabilization of their quaternary structure. These factors together probably contribute to the high propensity of A25T TTR to aggregate in vitro. The capacity of serum BChE-K to hydrolyze butyrylthiocholine was reported to be reduced by 30% relative to BChE-U, for yet unclear reasons (24Bartels C.F. Jensen F.S. Lockridge O. van der Spek A.F. Rubinstein H.M. Lubrano T. La Du B.N. Am. J. Hum. Genet. 1992; 50: 1086-1103PubMed Google Scholar). 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The BChE A and was determined from also serum for hydrolytic activity The and with the The hydrolytic of serum BChE from and The in hydrolytic activity from to carriers The of the A539T substitution in the C terminus, which is from the hydrolytic of the enzyme, that its impaired stability caused the reduced To this the stability of BChE-U and BChE-K was compared by serum from in of by and activity BChE-U and BChE-K are the activity of BChE-K tetramers was reduced in BChE-U, which was to this This that the hydrolytic activity was rapidly BChE-K tetramers the structural origin for the of BChE-K by the synthetic and for their with a rBChE-U Y. H. A. M. A. M. P. M. C. L. H. I. K. E. J. S. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: PubMed Scopus Google Scholar). a of with rBChE-U and BSP-U less not with and which not to the rBChE-U as an as a in all other did not or the peptides not These supported the of structural peptides and that tetramerization are of peptides studied by with the synthetic peptide, which BChE tetramerization (20Li H. Schopfer L.M. Masson P. Lockridge O. Biochem. J. 2008; 411: 425-432Crossref PubMed Scopus (84) Google Scholar). was used to both peptides interactions with by in the interactions has from it not in the region of the The of BSP-U was based on and and was the for of both peptides with of peptide to of of peptide in with the state are in BSP-U that the are more in this variant with The of the for residues and which and and which in both The interactions for peptides with their tetramerization with the reduced stability of BChE-K as compared with The C-terminal of both BChE and monomers are to the as based on the tetrameric structure of AChE-S of BChE and monomers used to the caused by C rBChE-U in the of yielded with as shown by Y. H. A. M. A. M. P. M. C. L. H. I. K. E. J. S. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: PubMed Scopus Google Scholar) was used to monomers from that of highly purified rBChE-U monomers and both fibril formation at a of to Aβ. and rBChE-U of the and in the fibril formation rBChE-U Aβ fibril formation more than the BChE and a and 20% less at the and the of fibril formation that recombinant BChE and yet more BChE from human serum attenuate this of this with the of a to with Aβ an and sustained the reduced in the thioflavin T both The structural of could potentially its to Aβ to β-sheet This was by Aβ or with peptides and the for of Aβ a in the of from to within In rBChE-U or peptides to Aβ the in β-sheet which an within to of Aβ oligomerization of Aβ in the or of BSP-U or and of the by Aβ within peptides prolonged the Aβ oligomers in BSP-U prolonged the of amyloid oligomers in more effectively than of forms of Aβ in the in the of in the of nearly This supports the that is less of both with and with Aβ than electron microscopy was used to and more Aβ in the or of rBChE-U and of Aβ with fibrils to In the of either of the the of Aβ fibrils long with than In the of a in the formation of fibrils of all was as compared with Aβ or with peptides of a decrease both in the and in the degree of of the fibrils in the of the peptides relative to of Aβ rBChE-U at reduced the of fibrils in a on the of rBChE-U for all fibril rBChE-U the of and the of fibrils by Of note, suppressed in the of not a of Aβ has been to oligomers Jr., J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., Teplow D.B. Neurobiol. 2004; PubMed Scopus Google Scholar). Aβ and the by peptides and rBChE-U was on cultured human neuroblastoma The cells in the of Aβ and in the of Aβ with peptides or an for a in from cells as compared with rBChE-U of this indicating that it the cells from the The peptides yielded only changes in that can only to attenuate Aβ fibril formation as an of the BChE and to the role of the BChE-K variant in Aβ which AD attribute of the for BChE-K carriers in AD to structural found BChE-K to be inherently unstable as compared with BChE-U, which elevated levels in its AD BChE-K was less in the accumulation of Aβ fibrils than in the alternative hypotheses for the role by Aβ in AD, that BChE-K either a risk or a factor in AD, in a by other It is that so that the in the are less than the attribute the BChE-K and AD to a structural with impaired stability and quaternary organization of BChE-K as compared with BChE-U and the suppressed hydrolytic by interactions with Aβ. This is supported by as The of BChE-K in AD studied (supplemental Table the of the A539T polymorphism within the tetramerization domain of BChE (16Altamirano C.V. Lockridge O. Chem. Biol. Interact. 1999; 119–120: 53-60Crossref PubMed Scopus (31) Google Scholar, 17Blong R.M. Bedows E. Lockridge O. Biochem. J. 1997; 327: 747-757Crossref PubMed Scopus (77) Google Scholar) has not been that the BChE-K C-terminal substitution both its stability and its This is supported by where tetrameric serum BChE is that BChE hydrolytic activity within at S. PubMed Scopus Google Scholar). peptides residues in of BSP-U as compared with only the changes in the BSP-U than in the indicating that organization in in residues that structural changes H. E. M. A.R. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: PubMed Scopus Google Scholar). The of the region and both a in the relative of the or a in the of the due to of the from due to the A539T to the Biochemistry. PubMed Scopus Google Scholar), is of the is of the β-sheet of is that the or the amphiphilic The of to is in the context of amyloidogenic as all amyloid fibrils a common structure. of a from an alanine-to-threonine substitution is the study that that the which in the terminus of the amphiphilic is more prone to than wild-type H. S. D. A. A. M. J. Mol. Biol. 2008; PubMed Scopus Google Scholar). In BChE-K, the would be by and of the could to of the of the pivotal tryptophan which we previously this amphiphilic to attenuate Aβ fibril formation (25Diamant S. Podoly E. Friedler A. Ligumsky H. Livnah O. Soreq H. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 8628-8633Crossref PubMed Scopus (147) Google Scholar). to structural interactions only it is located at the of an amphiphilic the becomes or is at the and the to be Aβ aggregation and only of oligomers are essential on the to fibril that formation would fibril formation as fibrils and oligomers aggregation oligomerization not fibril formation and Aβ oligomerization by and we fibril formation by In both rBChE-U and peptides both and fibril with This that the oligomers are fibril of the is that both rBChE-U and the peptides can a of Aβ accumulation a stabilized Aβ as as by the of The amyloid hypothesis that Aβ and a role in neuronal and in AD (15Hardy J. Selkoe D.J. Science. 2002; 297: 353-356Crossref PubMed Scopus (10962) Google Scholar, C. J. Mol. PubMed Scopus Google Scholar). that the of Aβ in its Jr., J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., Teplow D.B. Neurobiol. 2004; PubMed Scopus Google Scholar) rather than the fibrils that in AD Recent data that as as dimers, are the main neurotoxic in the pathogenesis of AD R.M. Bedows E. Lockridge O. Biochem. J. 1997; 327: 747-757Crossref PubMed Scopus (77) Google Scholar, A.L. Massoulié J. Krejci E. Neuron. 2002; 33: 275-285Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). that be by the of Aβ accumulation from the potentially more as by In and electron microscopy peptides Aβ less than displayed less than it with the Aβ monomers less The in interactions are to be in the rBChE-U protection from Aβ in cultured where the peptides to The Aβ and the membrane has been shown to be the in the chain of events that leads to A. E. I. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that rBChE-U interacts with the neurotoxic Aβ interactions are less This is with the hypothesis that BChE-U the of Aβ oligomers with the peptides are essential are to protection on their we that the rBChE-U to fibril with a by P. M.A. J. 2007; 93: Full Text Full Text PDF PubMed Scopus Google Scholar), to the of the fibril leads to of the fibril by this high of to Aβ and not the we in which a single rBChE-U can of Aβ that the the is by which structural due to the to and leads to of the structure of the The structural that BChE-K are that it less as a are to and for with