Amyloid-β induced membrane damage instigates tunneling nanotube-like conduits by p21-activated kinase dependent actin remodulation

Aysha Dilna, K. V. Deepak, Nandini Damodaran, Claudia S. Kielkopf, Katarina Kagedal, Karin Ollinger, Sangeeta Nath

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Alzheimer's disease (AD) pathology progresses gradually via anatomically connected brain regions. Direct transfer of amyloid-β142 oligomers (oAβ) between connected neurons has been shown, however, the mechanism is not fully revealed. We observed formation of oAβ induced tunneling nanotubes (TNTs)-like nanoscaled f-actin containing membrane conduits, in differentially differentiated SH-SY5Y neuronal models. Time-lapse images showed that oAβ propagate from one cell to another via TNT-like structures. Preceding the formation of TNT-like conduits, we detected oAβinduced plasma membrane (PM) damage and calcium-dependent repair through lysosomal-exocytosis, followed by massive endocytosis to re-establish the PM. Massive endocytosis was monitored by an influx of the membrane-staining dye TMA-DPH and PM damage was quantified by propidium iodide influx in the absence of Ca2+. The massive endocytosis eventually caused accumulation of internalized oAβ in Lamp1 positive multivesicular bodies/lysosomes via the actin cytoskeleton remodulating p21-activated kinase1 (PAK1) dependent endocytic pathway. Three-dimensional quantitative confocal imaging, structured illumination superresolution microscopy, and flowcytometry quantifications revealed that oAβ induces activation of phospho-PAK1, which modulates the formation of long stretched f-actin extensions between cells. Moreover, the formation of TNT-like conduits was inhibited by preventing PAK1-dependent internalization of oAβ using the small-molecule inhibitor IPA-3, a highly selective cell-permeable auto-regulatory inhibitor of PAK1. The present study reveals that the TNT-like conduits are probably instigated as a consequence of oAβ induced PM damage and repair process, followed by PAK1 dependent endocytosis and actin remodeling, probably to maintain cell surface expansion and/or membrane tension in equilibrium.

Original languageEnglish
Article number166246
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1867
Issue number12
DOIs
Publication statusPublished - 01-12-2021

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

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