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Direct Observations of Amyloid β Self-Assembly in Live Cells Provide Insights into Differences in the Kinetics of Aβ(1–40) and Aβ(1–42) Aggregation

Direct Observations of Amyloid β Self-Assembly in Live Cells Provide Insights into Differences in the Kinetics of Aβ(1–40) and Aβ(1–42) Aggregation, . Esbjörner E K, Chan F, Rees EJ, Erdelyi M, Luheshi LM, Bertoncini CW, Kaminski CF, Dobson CM, Kaminski-Schierle GS, Chemistry and Biology, (2014). DOI: 10.1016/j.chembiol.2014.03.014 | pdf


Abstract

Insight into how amyloid-β (Aβ) aggregation occurs in vivo is vital for an understanding of the molecular pathways that underlie Alzheimer’s disease. We imaged, therefore, the formation of Aβ(1-40) and Aβ(1-42) aggregates in live cells by non-invasive fluorescence lifetime recordings, following their endocytotic uptake. The kinetics of Aβ(1-42) aggregation was considerably faster than those of Aβ(1-40) and for Aβ(1-42) in particular we observed a reduced lag phase in the kinetic profile compared to in vitro. We estimated the size of intracellular Aβ assemblies at different incubation times by super-resolution imaging and show that this feature correlates well with their fluorescence lifetimes. These findings provide mechanistic understanding of how Aβ(1-40) and Aβ(1-42) aggregation can be promoted in neurons, and thus contribute to our knowledge of such behavior in the context of Alzheimer’s disease.

Highlights

Aggregation of fluorescently tagged Aβ can be monitored in live cells using Fluorescence Lifetime Imaging (FLIM)

Internalised Aβ(1-40) and Aβ(1-42) form amyloid fibrils in acidic organelles

Aβ40 and Aβ42 display different lag phases in vitro and in live cells

dSTORM provides details of the shape and size of Aβ aggregates in cells