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Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166246, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34403739

RESUMO

Alzheimer's disease (AD) pathology progresses gradually via anatomically connected brain regions. Direct transfer of amyloid-ß1-42 oligomers (oAß) between connected neurons has been shown, however, the mechanism is not fully revealed. We observed formation of oAß induced tunneling nanotubes (TNTs)-like nanoscaled f-actin containing membrane conduits, in differentially differentiated SH-SY5Y neuronal models. Time-lapse images showed that oAß propagate from one cell to another via TNT-like structures. Preceding the formation of TNT-like conduits, we detected oAß-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 oAß 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 oAß 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 oAß 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 oAß 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.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Dissulfetos/farmacologia , Naftóis/farmacologia , Quinases Ativadas por p21/genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/patologia , Endocitose/efeitos dos fármacos , Exocitose/efeitos dos fármacos , Humanos , Lisossomos/efeitos dos fármacos , Nanotubos/química , Quinases Ativadas por p21/antagonistas & inibidores
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