Amyloid-β induced membrane damage instigates tunnelling nanotubes and direct cell-to-cell transfer

The progressive pathology development in Alzheimer’s disease is due to direct transfer of amyloid-β oligomers (oAβ) between connected neurons. However, the mechanism of transfer is not revealed yet. Here we show that internalization of toxic oAβ in SH-SY5Y cells, causes cellular stress detected as significant membrane surface expansion. Subsequently, protrusions appear in the form of tunnelling nanotubes (TNTs). The TNTs propagate oAβ and organelles directly from one cell-to-another. Preceding the formation, we detect oAβ induced plasma membrane damage and repair through lysosomal-exocytosis followed by endocytosis to re-establish the membrane. Eventually, the non-degradable internalized oligomers accumulate in lysosomes. Direct transfer of neurodegenerative proteins via TNTs has recently been suggested as means of pathology spreading. However, molecular basis of TNTs formation is unexplored. The present study is giving the insight that sprouting of TNTs might instigate as consequences of oAβ induced membrane damage and perturbed membrane repair process in the stressed cells, probably to maintain cell surface expansion and/or membrane-tension in equilibrium.