Role of Membrane Tension Sensitive Endocytosis and Rho GTPases in the Uptake of the Alzheimer's Disease Peptide Aβ(1-42)
Journal article, 2020

Intraneuronal accumulation of amyloid-β (Aβ) is an early pathological signum of Alzheimer's disease, and compartments of the endolysosomal system have been implicated in both seeding and cell-cell propagation of Aβ aggregation. We have studied how clathrin-independent mechanisms contribute to Aβ endocytosis, exploring pathways that are sensitive to changes in membrane tension and the regulation of Rho GTPases. Using live cell confocal microscopy and flow cytometry, we show the uptake of monomeric Aβ(1-42) into endocytic vesicles and vacuole-like dilations, following relaxation of osmotic pressure-induced cell membrane tension. This indicates Aβ(1-42) uptake via clathrin independent carriers (CLICs), although overexpression of the bar-domain protein GRAF1, a key regulator of CLICs, had no apparent effect. We furthermore report reduced Aβ(1-42) uptake following overexpression of constitutively active forms of the Rho GTPases Cdc42 and RhoA, whereas modulation of Rac1, which is linked to macropinosome formation, had no effect. Our results confirm that uptake of Aβ(1-42) is clathrin-and dynamin-independent and point to the involvement of a new and distinct clathrin-independent endocytic mechanism which is similar to uptake via CLICs or macropinocytosis but that also appear to involve yet uncharacterized molecular players.

uptake mechanism

Aβ(1-42)

clathrin-independent endocytosis (CIE)

cellular uptake

Alzheimer's disease

Amyloid-β

Author

Emelie Vilhelmsson Wesén

Chalmers, Biology and Biological Engineering, Chemical Biology

Richard Lundmark

Umeå University

Elin Esbjörner Winters

Chalmers, Biology and Biological Engineering, Chemical Biology

ACS Chemical Neuroscience

1948-7193 (ISSN)

Vol. 11 13 1925-1936

Vad karaktäriserar en toxisk amyloid oligomer?

Swedish Research Council (VR), 2017-01-01 -- 2020-12-31.

Subject Categories

Cell Biology

Cell and Molecular Biology

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

DOI

10.1021/acschemneuro.0c00053

PubMed

32497421

More information

Latest update

9/17/2020