earticle

영어

Formation of amyloid-β (Aβ) aggregates is a core process in the pathogenesis of Alzheimer’s disease. Importance of interaction of the length variants, Aβ42 and Aβ40 in the process and consequent cytotoxicity has been pointed out for wild-type Aβ previously. In addition to confirming the findings, the current study demonstrates that the potential interaction is also important for cytotoxicity of the Flemish and Dutch sequence variants. The interaction could strengthen or inhibit cytotoxicity of Aβ42/Aβ40 mixture, depending on interaction time of the length variants as well as the ratio and amyloidogenic property. The inhibitory effect was prominent at the early stage of aggregate formation in less amyloidogenic Flemish Aβ42/Aβ40 mixture, while strengthened cytotoxicity was exhibited at the stage in potently amyloidogenic Dutch variant and at the later stage in wild-type and the Flemish variant. The samples showing relatively robust cytotoxicity were those enriched in Aβ protofibril-like structures, implying strong correlation of the structure with cytotoxicity. The different consequence of the interaction on sequence variants is likely due to differential amyloidogenic property of each Aβ40 variant, rather than that of Aβ42, because aggregation rates and levels of Aβ40 variants are greatly variable depending on the sequence, compared to Aβ42 variants. These studies may highlight a potential role of Aβ40 in the cytotoxicity, providing a novel mechanistic insight into the pathogenesis of each FAD-associated variant.