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bioRxiv · 10.1101/2025.02.11.637764

p21-activated kinase regulates Rab3a vesicles to repair plasma membrane damage caused by Amyloid-β oligomers

Valappil, D. K.·Veerabhadraswamy, P.·Sarathi, S. P.·Hegde, P.·Gowda, J. M.·KUMAR, A.·Gandasi, N. R.·Nath, S.
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Abstract

The interaction of amyloid-{beta} (A{beta}) peptides with the plasma membrane (PM) is a potential trigger that initiates the formation of higher-order aggregates, membrane alterations/damage, and progressive neurotoxicity in Alzheimers disease (AD). In a previous study, we showed that oligomers of A{beta}1-42 (oA{beta}1-42) induced PM damage, resulting in PM repair cascade via lysosomal exocytosis coupled with endocytosis, and facilitation of tunneling nanotubes (TNTs)-like membrane protrusions to promote direct cell-to-cell transfer of aggregates. In this study, we demonstrated that PM damage induced by oligomers of the aggregation-prone peptide A{beta}1-42 significantly facilitates PM repair by enhancing phosphorylated p21-activated kinase 1 (pPAK1)-dependent endocytosis and Rab3a-dependent exocytosis in SH-SY5Y and SK-N-SH neuronal cells compared to control and oA{beta}1-40 treated cells. We studied the kinetics of pPAK1-dependent endocytosis and the fusion of EGFP-Rab3a vesicles near the PM using total internal reflection fluorescence (TIRF) microscopy. IPA-3, a selective non-ATP competitive inhibitor of PAK1, inhibits endocytosis of oA{beta} peptides and Rab3a-dependent PM repair. Further, shRNA-mediated knockdown of the Rab3a gene inhibits pPAK1 and disrupts PM repair. Repair of damaged PM is a vital protective mechanism for non-proliferative cells like neurons, as disruption in PM repair leads to gradual neuronal cell death. However, there was no explicit understanding of PM repair in response to A{beta} oligomers. This study revealed the interconnected action of Rab3a and pPAK1 in PM repair in response to oA{beta}-mediated damage, and its potential correlation in AD pathogenesis.

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Valappil, D. K., Veerabhadraswamy, P., Sarathi, S. P., Hegde, P., Gowda, J. M., KUMAR, A., Gandasi, N. R., Nath, S.. 2025-02-15. p21-activated kinase regulates Rab3a vesicles to repair plasma membrane damage caused by Amyloid-β oligomers. https://doi.org/10.1101/2025.02.11.637764

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