Das, AnirbanGupta, AnkurHong, YuningCarver, JohnMaiti, Sudipta2023-02-010006-2960http://hdl.handle.net/1885/284111An amyloid aggregate evolves through a series of intermediates that have different secondary structures and intra- and intermolecular contacts. The structural parameters of these intermediates are important determinants of their toxicity. For example, the early oligomeric species of the amyloid-B (AB) peptide have been implicated as the most cytotoxic species in Alzheimer's disease but are difficult to identify because of their dynamic and transitory nature. Conventional aggregation monitors such as the fluorescent dye thioflavin T report on only the overall transition of the soluble species to the final amyloid fibrillar aggregated state. Here, we show that the fluorescent dye bis(triphenylphosphonium) tetraphenylethene (TPE-TPP) identifies at least three distinct aggregation intermediates of AB. Some atomic-level features of these intermediates are known from solid state nuclear magnetic resonance spectroscopy. Hence, the TPE-TPP fluorescence data may be interpreted in terms of these AB structural transitions. Steady state fluorescence and lifetime characteristics of TPE-TPP distinguish between the small oligomeric species (emission wavelength maximum, lambda max = 465 nm; average fluorescence lifetime, tauFl measured at 420 nm = 3.58 +- 0.04 ns), the intermediate species (lambda max = 452 nm; tauFl = 3.00 +- 0.03 ns), and the fibrils (lambda max = 406 nm; tauFl = 5.19 +- 0.08 ns). Thus, TPE-TPP provides a ready diagnostic for differentiating between the various, including the toxic, AB aggregates and potentially can be utilized to screen for amyloid aggregation inhibitors.This work was supported by Department of Atomic Energy, Government of India, Grant 12-R&D-TFR-5.10-0100- RTI2001. A.D. gratefully acknowledges the receipt of a Future Research Talent travel award from the Australian National Universityapplication/pdfen-AU© 2020 American Chemical Society202010.1021/acs.biochem.0c001132021-12-02