Neurotoxicity and Physicochemical Properties of Aβ Mutant Peptides from Cerebral Amyloid Angiopathy 论文

摘要

Cerebral amyloid angiopathy (CAA) due to β-amyloid (Aβ) is one of the specific pathological features of familial Alzheimer's disease. Aβ mainly consisting of 40- and 42-mer peptides (Aβ40 and Aβ42) exhibits neurotoxicity and aggregative abilities. All of the variants of Aβ40 and Aβ42 found in CAA were synthesized in a highly pure form and examined for neurotoxicity in PC12 cells and aggregative ability. All of the Aβ40 mutants at positions 22 and 23 showed stronger neurotoxicity than wild-type Aβ40. Similar tendency was observed for Aβ42 mutants at positions 22 and 23 whose neurotoxicity was 50-200 times stronger than that of the corresponding Aβ40 mutants, suggesting that these Aβ42 mutants are mainly involved in the pathogenesis of CAA. Although the aggregation of E22G-Aβ42 and D23N-Aβ42 was similar to that of wild-type Aβ42, E22Q-Aβ42 and E22K-Aβ42 aggregated extensively, supporting the clinical evidence that Dutch and Italian patients are diagnosed as hereditary cerebral hemorrhage with amyloidosis. In contrast, A21G mutation needs alternative explanation with the exception of physicochemical properties of Aβ mutants. Attenuated total reflection-Fourier transform infrared spectroscopy spectra suggested that β-sheet content of the Aβ mutants correlates with their aggregation. However, β-turn is also a critical secondary structure because residues at positions 22 and 23 that preferably form two-residue β-turn significantly enhanced the aggregative ability. Cerebral amyloid angiopathy (CAA) due to β-amyloid (Aβ) is one of the specific pathological features of familial Alzheimer's disease. Aβ mainly consisting of 40- and 42-mer peptides (Aβ40 and Aβ42) exhibits neurotoxicity and aggregative abilities. All of the variants of Aβ40 and Aβ42 found in CAA were synthesized in a highly pure form and examined for neurotoxicity in PC12 cells and aggregative ability. All of the Aβ40 mutants at positions 22 and 23 showed stronger neurotoxicity than wild-type Aβ40. Similar tendency was observed for Aβ42 mutants at positions 22 and 23 whose neurotoxicity was 50-200 times stronger than that of the corresponding Aβ40 mutants, suggesting that these Aβ42 mutants are mainly involved in the pathogenesis of CAA. Although the aggregation of E22G-Aβ42 and D23N-Aβ42 was similar to that of wild-type Aβ42, E22Q-Aβ42 and E22K-Aβ42 aggregated extensively, supporting the clinical evidence that Dutch and Italian patients are diagnosed as hereditary cerebral hemorrhage with amyloidosis. In contrast, A21G mutation needs alternative explanation with the exception of physicochemical properties of Aβ mutants. Attenuated total reflection-Fourier transform infrared spectroscopy spectra suggested that β-sheet content of the Aβ mutants correlates with their aggregation. However, β-turn is also a critical secondary structure because residues at positions 22 and 23 that preferably form two-residue β-turn significantly enhanced the aggregative ability. Alzheimer's disease (AD)1 is neuropathologically characterized by the progressive deposition of amyloid in the brain parenchyma and cortical blood vessels (1Selkoe D.J. Trends Cell Biol. 1998; 8: 447-453Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar). This deposition mainly consists of 40- and 42-mer β-amyloid peptides (Aβ40 and Aβ42) generated from amyloid precursor protein by two proteases, β- and γ-secretases (2Iwatsubo T. Odaka A. Suzuki N. Mizusawa H. Nukina N. Ihara Y. Neuron. 1994; 13: 45-53Abstract Full Text PDF PubMed Scopus (1523) Google Scholar, 3Iwatsubo T. Mann D.M.A. Odaka A. Suzuki N. Ihara Y. Ann. Neurol. 1995; 37: 294-299Crossref PubMed Scopus (334) Google Scholar). Cerebral amyloid angiopathy (CAA) in familial Alzheimer's disease is linked to missense mutations inside the Aβ-coding region in the amyloid precursor protein. The mutations of Aβ sequence are concentrated at positions 21-23 and are called Flemish (A21G) (4Hendriks L. van Duijn C.M. Cras P. Cruts M. van Hul W. van Harskamp F. Warren A. McInnis M.G. Antonarakis S.E. Martin J.-J. Hofman A. van Broeckhoven C. Nat. Genet. 1992; 1: 218-221Crossref PubMed Scopus (640) Google Scholar), Arctic (E22G) (5Nilsberth C. Westlind-Danielsson A. Eckman C.B. Condron M.M. Axelman K. Forsell C. Stenh C. Luthman J. Teplow D.B. Younkin S.G. Naslund J. Lannfelt L. Nature Neurosci. 2001; 4: 887-893Crossref PubMed Scopus (887) Google Scholar, 6Kamino K. Orr H.T. Payami H. Wijsman E.M. Alonso M.E. Pulst S.M. Anderson L. O'dahl S. Nemens E. White J.A. Sadovnick A.D. Ball M.J. Kaye J. Warren A. Mclnnis M. Antonarakis S.E. Korenberg J.R. Sharma V. Kukull W. Larson E. Heston L.L. Martin G.M. Bird T.D. Schellenberg G.D. Am. J. Hum. Genet. 1992; 51: 998-1014PubMed Google Scholar), Dutch (E22Q) (7Levy E. Carman M.D. Fernandez-Madrid I.J. Power M.D. Lieberburg I. van Duinen S.G. Bots G.Th.A.M. Luyendijk W. Frangione B. Science. 1990; 248: 1124-1126Crossref PubMed Scopus (1147) Google Scholar), Italian (E22K) (8Tagliavini F. Rossi G. Padovani A. Magoni M. Andora G. Sgarzi M. Bizzi A. Savoiardo M. Carella F. Morbin M. Giaccone G. Bugiani O. Alzheimer's Rep. 1999; 2: S28Google Scholar), and Iowa (D23N) (9Grabowski T.J. Cho H.S. Vonsattel J.P.G. Rebeck G.W. Greenberg S.M. Ann. Neurol. 2001; 49: 697-705Crossref PubMed Scopus (423) Google Scholar) mutations. These Aβ mutant peptides may play a pathological role in the CAAs because wild-type Aβ peptides induce neuronal death in vitro (10Pike C.J. Burdick D. Walencewicz A.J. Glabe C.G. Cotman C.W. J. Neurosci. 1993; 13: 1676-1687Crossref PubMed Google Scholar). Neurotoxicity and formation of amyloid fibrils of some CAA-related Aβ40 mutants have been independently reported by several groups (11Davis J. van Nostrand W.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 2996-3000Crossref PubMed Scopus (158) Google Scholar, 12Miravalle L. Tokuda T. Chiarle R. Giaccone G. Bugiani O. Tagliavini F. Frangione B. Ghiso J. J. Biol. Chem. 2000; 275: 27110-27116Abstract Full Text Full Text PDF PubMed Google Scholar, 13Melchor J.P. McVoy L. van Nostrand W.E. J. Neurochem. 2000; 74: 2209-2212Crossref PubMed Scopus (104) Google Scholar, 14Wang Z. Natté R. Berliner J.A. van Duinen S.G. Vinters H.V. Stroke. 2000; 31: 534-538Crossref PubMed Scopus (58) Google Scholar, 15van Nostrand W.E. Melchor J.P. Cho H.S. Greenberg S.M. Rebeck G.W. J. Biol. Chem. 2001; 276: 32860-32866Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar). However, there are no reports on the neurotoxicity and aggregation of the CAA-related Aβ42 mutants with the exception of Dutch mutation (E22Q) (11Davis J. van Nostrand W.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 2996-3000Crossref PubMed Scopus (158) Google Scholar), the investigation of which is essential to reveal the mechanism of CAA because wild-type Aβ42 shows considerably stronger neurotoxicity and aggregative ability than wild-type Aβ40 (11Davis J. van Nostrand W.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 2996-3000Crossref PubMed Scopus (158) Google Scholar). Moreover, it is indispensable to simultaneously compare neurotoxicity and aggregative ability of all of the CAA-related Aβ40 and Aβ42 mutants in the same conditions such as pH, peptide concentration, reaction buffer, and temperature. It is difficult to synthesize Aβ42 with 14 hydrophobic residues at the in a highly pure because it and conditions D. B. M. J. M. A. J. Cotman C. Glabe C. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). a highly for peptides residues with a peptide J. Am. Chem. 1993; Scopus Google Scholar) as for K. K. A. Y. H. H. H. U. J. Am. Chem. 1998; Scopus Google Scholar, H. T. M. H. T. Chem. 1999; PubMed Scopus Google Scholar, H. K. A. H. Chem. 1999; Scopus Google Scholar, M. K. A. H. H. U. H. Chem. 2001; Scopus Google Scholar, T. H. S. N. T. J. Neurosci. PubMed Scopus Google Scholar). This to the CAA-related Aβ42 mutants with in with the the K. K. A. H. M. M. T. T. PubMed Scopus Google Scholar). on the CAA-related Aβ peptides to the of all of the CAA-related Aβ40 and Aβ42 mutants at positions 21-23 and at positions 22 and 23 of CAA-related Aβ mutants are found in a two-residue β-turn G.D. J. Biol. PubMed Scopus (887) Google Scholar), synthesized several Aβ40 and Aβ42 at 22 by the which the formation of the two-residue β-turn as and residues in the as β-turn and and residues as β-turn G.D. J. Biol. PubMed Scopus (887) Google Scholar). 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The reaction was and in for the was with in of the with and was with a and for and from the of at the peptide by was by conditions as reported H. T. M. H. T. Chem. 1999; PubMed Scopus Google Scholar, T. H. S. N. T. J. Neurosci. PubMed Scopus Google Scholar, K. K. A. H. M. M. T. T. PubMed Scopus Google Scholar). a corresponding pure Aβ the of which was by Cell of PC12 PC12 cells were from Cell and were as reported K. K. A. H. M. M. T. T. PubMed Scopus Google Scholar). of the cells were at in with and at PC12 of by was by the on a L.L. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar) with of Aβ by the was with at from to of the and of to the which was at for of from the of in the was to the which was at for of the the was to the cells and the was in the at temperature. The of was at The by the of was as for Aβ was in at a by at the peptide was at for at in at for of the was by as reported K. K. A. H. M. M. T. T. PubMed Scopus Google Scholar). The of the at was and as a of the Aβ was in at The peptide with the was at for of Aβ was to of in was at and as reported H. F. 1999; PubMed Scopus Google Scholar). of of Aβ42 formation of the Aβ42 was by Aβ42 was in buffer, for at the was from were in by These were to a and to in for with were examined with the to the of Aβ42 Aβ42 was in buffer, at The Aβ42 was at for The was at in at for and the was The was in and to a which was on in the the same Aβ42 was also to the were to the and the spectra were at a of The was to the secondary structure of by of Aβ CAA-related Aβ40 and Aβ42 mutants at positions 21-23 were synthesized to their to the pathogenesis of these CAAs Aβ in which the of wild-type Aβ was by residues and that the formation of the two-residue β-turn G.D. J. Biol. 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The of the Aβ to the formation from to as in in cells of Aβ by the in a Aβ40 the formation at wild-type Aβ42 considerably it at All of the CAA-related Aβ40 mutants at 22 significantly the formation at the at The CAA-related Aβ42 mutants at 22 and also showed the neurotoxicity of wild-type of of the formation was D23N-Aβ42 mutant at 23 showed than wild-type showed a on the PC12 cells with wild-type Aβ42 aggregative ability of Aβ by of the Aβ peptide Aβ are also which to the to H. K. M. T. PubMed Scopus Google Scholar). of the is that it is because on the structure and of the The is for of the of all wild-type Aβ40 was by the that wild-type Aβ40 aggregated by This is in with that of the The of Aβ40 was to that of the the wild-type Aβ42 by the that wild-type Aβ42 aggregated This with that of the the These that the aggregative ability of Aβ42 is than that of and their aggregative ability correlates with their of the aggregation of CAA-related Aβ42 mutants at positions 21-23 by wild-type E22G-Aβ42 E22Q-Aβ42 E22K-Aβ42 and D23N-Aβ42 of the aggregation of CAA-related Aβ42 mutants at positions 21-23 by H. F. 1999; PubMed Scopus Google Scholar). The the at of the aggregation of Aβ at 22 by of the aggregation of Aβ at 22 by H. F. 1999; PubMed Scopus Google Scholar). wild-type and all of the CAA-related Aβ40 mutants at and aggregated than wild-type Aβ40 as in and the aggregative of the Aβ40 mutants at 22 was than that of the Aβ40 mutant at the in the aggregative ability Aβ40 and Aβ42, the aggregative ability of all of the Aβ40 mutants at 22 to that of wild-type showed a the of and their aggregative in the The aggregative of was the Aβ40 mutants and the of peptide was also than that of wild-type Aβ40 The aggregative ability of all of the Aβ40 mutants by the with their neurotoxicity ability of the CAA-related Aβ42 mutants is in E22Q-Aβ42 and E22K-Aβ42 aggregated than wild-type Aβ42 in the Although the aggregative of E22G-Aβ42 and D23N-Aβ42 was than that of wild-type Aβ42, the aggregative of E22G-Aβ42 was similar to that of wild-type Aβ42 and the aggregated of D23N-Aβ42 was with that of wild-type Aβ42 of all of the Aβ42 mutants at positions 22 and 23 was and these of the The aggregative ability of Aβ42 mutants at positions 22 and 23 examined by with their neurotoxicity However, with a neurotoxicity aggregated and showed no peptide the that the aggregative ability of the peptide correlates with of of Aβ42 formation of the Aβ42 mutants was by a at fibrils were in all of the CAA-related Aβ42 mutants with the exception of which at all as The of these fibrils However, the of the D23N-Aβ42 was than that of the of the Aβ42 are to a of the β-sheet structure D.B. 1998; PubMed Scopus Google Scholar). the secondary structure of the Aβ mutants, was on the CAA-related Aβ42 Aβ42 mutant in buffer, a in the same at was to the The of the Aβ42 mutants at positions 22 and 23 a and corresponding to the β-sheet structure E. V. Scholar). The secondary from the in these spectra the are in All of the CAA-related Aβ42 mutants at positions 22 and 23 β-sheet content than wild-type Aβ42 The β-sheet content of E22K-Aβ42 with aggregative ability was that of with aggregative was significantly than that of the Aβ mutants and was for structure of Aβ by their in a In all of the fibrils of the Aβ mutants, of the and significantly that the β-sheet content by The β-sheet content of the fibrils of the Aβ mutants the aggregative by the The β-sheet content of the E22K-Aβ42 fibrils was that of the E22G-Aβ42 and D23N-Aβ42 was than that of wild-type and of Aβ at and are found in the two-residue β-turn G.D. J. Biol. 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PubMed Scopus (887) Google Scholar). and showed stronger neurotoxicity with aggregative ability than the corresponding wild-type Aβ42 and and The neurotoxicity and aggregative ability of were considerably stronger than of and were with of E22Q-Aβ42 and E22K-Aβ42 and and spectra of a and with a and because of and structure of the spectra the showed β-sheet content than wild-type Aβ42 with neurotoxicity and aggregative ability. also fibrils similar to of wild-type Aβ42 as in β-sheet content of fibrils was suggested by the of the that the formation at positions 22 and 23 significantly β-sheet content of these Aβ the the neurotoxicity and aggregative ability of were a is found in the two-residue formation at positions 22 and 23 to critical for the neurotoxicity and aggregative ability of Aβ to the neurotoxicity and aggregative ability of and because of their in the Neurotoxicity of Aβ is significantly in the pathogenesis of neuronal in on Aβ the mechanism been it is that wild-type Aβ shows neurotoxicity in vitro mainly of the aggregative a it is indispensable to reveal the pathological of Aβ peptides that to neurotoxicity and aggregation. on the inside mutations of Aβ in CAA because these mutations may to the neurotoxicity of the Aβ to the for peptide K. 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The Dutch and Italian patients cerebral amyloid are and are This of the Dutch and Italian patients from that of the Arctic and Iowa patients L. Tokuda T. Chiarle R. Giaccone G. Bugiani O. Tagliavini F. Frangione B. Ghiso J. J. Biol. Chem. 2000; 275: 27110-27116Abstract Full Text Full Text PDF PubMed Google Scholar) and with the aggregative ability of the corresponding Aβ mutants. It been reported that than E22Q-Aβ42 a role in CAA because E22Q-Aβ42 (11Davis J. van Nostrand W.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 2996-3000Crossref PubMed Scopus (158) Google Scholar). However, the of E22Q-Aβ42 the Aβ42 mutants. In wild-type Aβ42 aggregated than wild-type from the of groups (11Davis J. van Nostrand W.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 2996-3000Crossref PubMed Scopus (158) Google Scholar, K. A. T. J. J. Neurosci. PubMed Google Scholar, M.D. Condron M.M. Teplow D.B. J. Biol. 2001; PubMed Scopus Google Scholar, A. H. T. T. I. S. K. N. J. 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The shows that the residues a of the that the two in formation at positions and is because sequence is found in the two-residue β-turn G.D. J. Biol. PubMed Scopus (887) Google Scholar). Although the of the the positions are from the Y. F. R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). the structure at positions and peptides were synthesized and examined for their aggregative ability. However, these peptides aggregated of wild-type Aβ42 by the and were than wild-type Aβ42 suggesting that positions of Aβ42 are involved in the β-sheet formation than the formation because are in the G.D. J. Biol. PubMed Scopus (887) Google Scholar, G.D. 13: PubMed Scopus Google Scholar). Aβ42 is highly than the pathological of Aβ42 from that of the Aβ40. It is also that the pathological of the CAA-related Aβ is from that of wild-type Aβ40. In the the at positions and is by of the residues and at positions 22 and 23 of Aβ E22K-Aβ42 and D23N-Aβ42 to the from and to positions 22 and 23 This which the β-sheet the aggregative ability of Aβ In the highly pure Aβ mutants that Aβ42 mutants at positions 22 and 23 play a role in the pathogenesis of the CAAs than the corresponding Aβ40 mutants. The secondary structure of these Aβ and the of Aβ42 to the that β-turn at positions 22 and 23 is the secondary structure to neurotoxicity and aggregative ability of Aβ This also CAA mutations are concentrated at positions 22 and 23 of Aβ The in neurotoxicity and aggregative ability of Aβ42 and Aβ40 peptides also the of the two The that the residues at positions 22 and 23 and and to the aggregation mechanism of Aβ peptides and to which the aggregation of of Aβ one of the to with the of Aβ42 is in of peptide was on the of a The in were with a in the and one of The of the spectra to in a all of the were In of the secondary structure of Aβ42 the of the was The spectra of wild-type Aβ42 and E. and that in because of conditions concentration, pH, and Aβ42 highly pure Aβ42 by the Aβ42 is the conditions the of Aβ42 is to The for of peptide secondary structure was to the reported R. and W. C. In the were from the spectra from to of and the secondary structure and were from the of the is a that the β-sheet and are because it been that of the secondary structure of Aβ peptides from the However, have evidence of of the β-sheet structure in several Aβ42 mutants by spectra with the exception of which K. K. A. H. M. M. T. T. PubMed Scopus Google Scholar). The of the in was the same was several wild-type Aβ42 was on by the same the was In there is due to that of of the secondary This the of the β-sheet with wild-type at for the