Endocytic uptake of monomeric amyloid-β peptides is clathrin- and dynamin-independent and results in selective accumulation of Aβ(1-42) compared to Aβ(1-40)

Scientific Reports
Emelie WesénElin K Esbjörner

Abstract

Intraneuronal accumulation of amyloid-β (Aβ) peptides represent an early pathological feature in Alzheimer's disease. We have therefore utilized flow cytometry and confocal microscopy in combination with endocytosis inhibition to explore the internalisation efficiency and uptake mechanisms of Aβ(1-40) and Aβ(1-42) monomers in cultured SH-SY5Y cells. We find that both variants are constitutively internalised via endocytosis and that their uptake is proportional to cellular endocytic rate. Moreover, SH-SY5Y cells internalise consistently twice the amount of Aβ(1-42) compared to Aβ(1-40); an imaging-based quantification showed that cells treated with 1 µM peptide for 8 h contained 800,000 peptides of Aβ(1-42) and 400,000 of Aβ(1-40). Both variants co-localised to >90% with lysosomes or other acidic compartments. Dynasore and chlorpromazine endocytosis inhibitors were both found to reduce uptake, particularly of Aβ(1-42). Overexpression of the C-terminal of the clathrin-binding domain of AP180, dynamin2 K44A, or Arf6 Q67L did however not reduce uptake of the Aβ variants. By contrast, perturbation of actin polymerisation and inhibition of macropinocytosis reduced Aβ(1-40) and Aβ(1-42) uptake considerably. This study clarifies mechan...Continue Reading

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Citations

Feb 7, 2018·Scientific Reports·Matthew MoldChristopher Exley
Dec 15, 2018·Chembiochem : a European Journal of Chemical Biology·Subrata DuttaJevgenij A Raskatov
Feb 8, 2020·Journal of Neural Transmission·Jelena Osmanovic BarilarMelita Salkovic-Petrisic
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Jun 24, 2020·Biomolecules·Nima SasanianElin K Esbjörner
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Feb 6, 2019·Scientific Reports·Tamás LetohaLászló Szilák
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Feb 15, 2019·ACS Chemical Neuroscience·Barun Kumar MaitySudipta Maiti

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Methods Mentioned

BETA
flow cytometry
Confocal microscopy
Flow
fluorescence microscopy
transfection
GTPase
confocal

Software Mentioned

Origin
JACoP
FlowJo
ImageJ
ThorImageLS
GraphPad Prism
InCyte

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