{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:41:26Z","timestamp":1791114086487,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2014,5,6]],"date-time":"2014-05-06T00:00:00Z","timestamp":1399334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2014,6]]},"abstract":"Fibrillar amyloid\u2010\u03b2 (A\u03b2) is the major constituent of senile plaques in the brain of patients with Alzheimer's disease (AD<\/jats:styled-content>). A\u03b2 is a short peptide generated from amyloid precursor protein with two main isoforms, A\u03b240 and A\u03b242, with the latter having two additional hydrophobic residues at the C\u2010terminus. The two isoforms have distinct characteristics, in which A\u03b242 plays a more pathogenic role. Some early\u2010onset familial AD<\/jats:styled-content> cases possess an elevated A\u03b242\/A\u03b240 level, and biochemical studies show the two species interact with each other. Therefore, understanding structural conversion in the aggregation of mixed A\u03b2 isoforms is essential for elucidating AD<\/jats:styled-content> pathogenesis. Here, we systematically examined the differences between A\u03b242, A\u03b240 and various A\u03b242\/A\u03b240 mixtures by monitoring the fibrillization kinetics, epitope changes, assembly, morphology and induced cytotoxicity. We found that the minor A\u03b2 species in different mixing ratios modulated the major aggregation pathway. Size exclusion chromatography, circular dichroism spectroscopy and photo\u2010crosslinking assay showed that soluble A\u03b242 oligomers were stabilized after A\u03b240 addition, and the equimolar A\u03b242\/A\u03b240 mixture rapidly formed spherical oligomers. These oligomers were the most toxic among those examined as evidenced by neurite degeneration and neuronal toxicity. However, the oligomers were not responsible for intracellular calcium elevation. Overall, our results demonstrated that differently mixed A\u03b2 species repartitioned oligomer intermediates on the major aggregation pathway. Furthermore, the equimolar mixture rapidly formed structurally stable and the most toxic oligomers. These results provided information on the potential pathological mechanisms underlying the elevated A\u03b242\/A\u03b240 ratio in familial AD<\/jats:styled-content> patients and in the local environment of sporadic AD<\/jats:styled-content> brains.<\/jats:p><\/jats:sec>Structured digital abstract<\/jats:title>\n\n\n Abeta40<\/jats:ext-link>\u00a0and\u00a0Abeta42<\/jats:ext-link>\u00a0bind<\/jats:ext-link>\u00a0by\u00a0fluorescence technology<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>); by\u00a0filter binding<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>); by\u00a0electron microscopy<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>); by\u00a0molecular sieving<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>) and by\u00a0cross-linking study<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>)<\/jats:p><\/jats:list-item>\n\n Abeta42<\/jats:ext-link>\u00a0and\u00a0Abeta42<\/jats:ext-link>\u00a0bind<\/jats:ext-link>\u00a0by\u00a0fluorescence technology<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>); by\u00a0filter binding<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>); by\u00a0electron microscopy<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>); by\u00a0molecular sieving<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>) and by\u00a0cross-linking study<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>)<\/jats:p><\/jats:list-item>\n\n Abeta40<\/jats:ext-link>\u00a0and\u00a0Abeta40<\/jats:ext-link>\u00a0bind<\/jats:ext-link>\u00a0by\u00a0fluorescence technology<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>); by\u00a0filter binding<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>); by\u00a0electron microscopy<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>); by\u00a0molecular sieving<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>) and by\u00a0cross-linking study<\/jats:ext-link>\u00a0(View interaction<\/jats:ext-link>)<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.12813","type":"journal-article","created":{"date-parts":[[2014,4,10]],"date-time":"2014-04-10T23:50:51Z","timestamp":1397173851000},"page":"2674-2687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["The coexistence of an equal amount of Alzheimer's amyloid\u2010\u03b2 40 and 42 forms structurally stable and toxic oligomers through a distinct pathway"],"prefix":"10.1111","volume":"281","author":[{"given":"Yu\u2010Jen","family":"Chang","sequence":"first","affiliation":[{"name":"Genomics Research Center Academia Sinica Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun\u2010Ru","family":"Chen","sequence":"additional","affiliation":[{"name":"Genomics Research Center Academia Sinica Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,5,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0909142"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genom.3.022502.103022"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04533"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M201750200"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1799"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2101"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R800036200"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1017033108"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3537-10.2010"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C400260200"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M500997200"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2008.02.016"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/359325a0"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi802046n"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2007.01.007"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1105850"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(94)80591-0"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.02.093"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M602363200"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.222681699"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.247"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.12.043"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja8092604"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M803159200"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi991161m"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.04.014"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.264473"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.211"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4849-06.2007"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1021910729963"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2010.01137.x"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1079469"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-2-18"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.069542"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.35.22364"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M102223200"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2007.04.021"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905127106"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2008.03.022"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.181313"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.000208"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1237107100"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2010-1301"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2009.12.010"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(98)01272-4"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.22.10836"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-010-0690-1"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)48529-8"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00859a010"}],"container-title":["The 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