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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)

Emelie Lindahl Wesén (Institutionen för biologi och bioteknik, Kemisk biologi) ; Gavin D.M. Jeffries ; Maria Matson Dzebo (Institutionen för biologi och bioteknik, Kemisk biologi) ; Elin Esbjörner (Institutionen för biologi och bioteknik, Kemisk biologi)
Scientific Reports (20452322). Vol. 7 (2017), 1, p. Article number 2021.
[Artikel, refereegranskad vetenskaplig]

Intraneuronal accumulation of amyloid-? (A?) 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 A?(1-40) and A?(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 A?(1-42) compared to A?(1-40); an imaging-based quantification showed that cells treated with 1 ?M peptide for 8 h contained 800,000 peptides of A?(1-42) and 400,000 of A?(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 A?(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 A? variants. By contrast, perturbation of actin polymerisation and inhibition of macropinocytosis reduced A?(1-40) and A?(1-42) uptake considerably. This study clarifies mechanisms of A?(1-40) and A?(1-42) uptake, pinpoints differences between the two variants and highlights a common and putative role of macropinocytosis in the early accumulation of intraneuronal A? in AD. © 2017 The Author(s).

Denna post skapades 2017-06-13. Senast ändrad 2017-07-27.
CPL Pubid: 249746


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