Amyloid-β induced membrane damage instigates tunneling nanotubes by exploiting p21-activated kinase dependent actin remodulation

Abstract

The progressive pathology development in Alzheimer's disease is due to direct 12 transfer of amyloid-β1-42 oligomers (oAβ) between connected neurons. However, the 13 mechanism of transfer is not revealed yet. Here we show that internalization of toxic oAβ in 14 SH-SY5Y cells, causes cellular stress detected as significant membrane surface expansion. 15 Subsequently, protrusions appear in the form of tunnelling nanotubes (TNTs). The TNTs 16 propagate oAβ and organelles directly from one cell-to-another. Preceding the formation, we 17 detect oAβ induced plasma membrane damage and repair through lysosomal-exocytosis 18 followed by endocytosis to re-establish the membrane. Eventually, the non-degradable 19 internalized oligomers accumulate in lysosomes. Direct transfer of neurodegenerative proteins 20 via TNTs has recently been suggested as means of pathology spreading. However, molecular 21 basis of TNTs formation is unexplored. The present study is giving the insight that sprouting 22 of TNTs might instigate as consequences of oAβ induced membrane damage and perturbed 23 membrane repair process in the stressed cells, probably to maintain cell surface expansion 24 and/or membrane-tension in equilibrium. 25 26 Summary: TNTs were recently discovered as novel route in cell-to-cell pathology spreading 27 of many diseases. Here we show that TNTs instigate as a consequences of perturbed membrane 28 repair process in oAβ accumulated stressed cells. The mechanistic understanding has enormous 29 pathophysiology significance.30 31 Short title: Direct cell-to-cell transfer of Aβ oligomers in TNTs. 32 33 2

Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells

“…We used multiple breast cancer cell lines to show for the first time that p38 is a direct regulator of TNT formation. However, indirect targeting of p38, by blocking its upstream activator PAK1 with the drug IPA-3, inhibits TNT formation in a neuroblastoma cell line [ 101 ]. Moreover, the truncated form of Cx43 stimulates filopodia formation by activating p38 through phosphorylation of the upstream target PAK1, with filopodia formation significantly reduced via IPA-3 inhibition of PAK1 activity [ 76 ].…”

Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells

“…direct regulator of TNT formation. However, indirect targeting of p38, by blocking its upstream activator PAK1 with the drug IPA-3, inhibits TNT formation in a neuroblastoma cell line [101]. Moreover, the truncated form of Cx43 stimulates filopodia formation by activating p38 through phosphorylation of the upstream target PAK1, with filopodia formation significantly reduced via IPA-3 inhibition of PAK1 activity [76].…”

Tunneling Nanotubes: A New Target for Nanomedicine?

“…The natural exchange of different materials from one cell to another is an evolutionary defensive strategy to reduce the risk of cell death: on one hand, a healthy cell could share its organelles with a diseased one to promote damage repair [45,46] or improve cell respiration by the transfer of mitochondria in case of hypoxia [47]; on the other hand, this can also be used by cells in an attempt to dilute stressful inputs, leading to an increased number of stressed cells but lower stress levels. However, these mechanisms are also exploited and enhanced by numerous viruses, such as HIV [48], herpesviruses [49,50], influenza viruses [51,52], and more recently, SARS-CoV-2 [51,53,54].…”