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

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. 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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). 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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. 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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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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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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