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Amyloid-beta induced membrane damage instigates tunneling nanotube-like conduits by p21-activated kinase dependent actin remodulation
Manipal Acad Higher Educ, India.
Manipal Acad Higher Educ, India.
Manipal Acad Higher Educ, India.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Copenhagen, Denmark.
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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
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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)

Available from: 2021-10-05 Created: 2021-10-05 Last updated: 2022-05-25

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