Amyloid-beta induced membrane damage instigates tunneling nanotube-like conduits by p21-activated kinase dependent actin remodulationShow others and affiliations
2021 (English)In: Biochimica et Biophysica Acta - Molecular Basis of Disease, ISSN 0925-4439, E-ISSN 1879-260X, Vol. 1867, no 12, article id 166246Article in journal (Refereed) Published
Abstract [en]
Alzheimers disease (AD) pathology progresses gradually via anatomically connected brain regions. Direct transfer of amyloid-beta(1-42) oligomers (oA beta) between connected neurons has been shown, however, the mechanism is not fully revealed. We observed formation of oA beta induced tunneling nanotubes (TNTs)-like nanoscaled f-actin containing membrane conduits, in differentially differentiated SH-SY5Y neuronal models. Time-lapse images showed that oA beta propagate from one cell to another via TNT-like structures. Preceding the formation of TNT-like conduits, we detected oA beta_induced 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 oA beta 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 oA beta 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 oA beta 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 oA beta 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.
Place, publisher, year, edition, pages
ELSEVIER , 2021. Vol. 1867, no 12, article id 166246
Keywords [en]
Alzheimers disease; Tunneling nanotubes; Amyloid-beta; Lysosomal-exocytosis; Clathrin-independent endocytosis; p21-activated kinase; Prion-like propagation
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-179823DOI: 10.1016/j.bbadis.2021.166246ISI: 000697154300008PubMedID: 34403739OAI: oai:DiVA.org:liu-179823DiVA, id: diva2:1600458
Note
Funding Agencies|Manipal Academy of Higher Education (India) [MAHE/CDS/PHD/MIFR/2019]; Magnus Bergvalls (Sweden) [2014-00192]; Manipal Academy of Higher Education; Gun och Bertil Stohnes research grants (Sweden, 2014-2015)
2021-10-052021-10-052022-05-25