Structural progression of amyloid-? Arctic mutant aggregation in cells revealed by multiparametric imaging.

ABSTRACT: The 42-amino-acid ?-amyloid (A?42) is a critical causative agent in the pathology of Alzheimer's disease. The hereditary Arctic mutation of A?42 (E22G) leads to increased intracellular accumulation of ?-amyloid in early-onset Alzheimer's disease. However, it remains largely unknown how the Arctic mutant variant leads to aggressive protein aggregation and increased intracellular toxicity. Here, we constructed stable cell lines expressing fluorescent-tagged wildtype (WT) and E22G A?42 to study the aggregation kinetics of the Arctic A?42 mutant peptide and its heterogeneous structural forms. Arctic-mutant peptides assemble and form fibrils at a much faster rate than WT peptides. We identified five categories of intracellular aggregate-oligomers, single fibrils, fibril bundles, clusters, and aggresomes-that underline the heterogeneity of these A?42 aggregates and represent the progression of A?42 aggregation within the cell. Fluorescence-lifetime imaging (FLIM) and 3D structural illumination microscopy (SIM) showed that all aggregate species displayed highly compact structures with strong affinity between individual fibrils. We also found that aggregates formed by Arctic mutant A?42 were more resistant to intracellular degradation than their WT counterparts. Our findings uncover the structural basis of the progression of Arctic mutant A?42 aggregation in the cell.

SUBMITTER: Lu M 

PROVIDER: S-EPMC6364760 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature