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Endosome and Lysosome Membrane Properties Functionally Link to γ-Secretase in Live/Intact Cells

Our unique multiplexed imaging assays employing FRET biosensors have previously detected that γ-secretase processes APP C99 primarily in late endosomes and lysosomes in live/intact neurons. Moreover we have shown that Aβ peptides are enriched in the same subcellular loci. Given that γ-secretase is i...

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Autores principales: Houser, Mei C. Q., Mitchell, Shane P. C., Sinha, Priyanka, Lundin, Brianna, Berezovska, Oksana, Maesako, Masato
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10007619/
https://www.ncbi.nlm.nih.gov/pubmed/36904854
http://dx.doi.org/10.3390/s23052651
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author Houser, Mei C. Q.
Mitchell, Shane P. C.
Sinha, Priyanka
Lundin, Brianna
Berezovska, Oksana
Maesako, Masato
author_facet Houser, Mei C. Q.
Mitchell, Shane P. C.
Sinha, Priyanka
Lundin, Brianna
Berezovska, Oksana
Maesako, Masato
author_sort Houser, Mei C. Q.
collection PubMed
description Our unique multiplexed imaging assays employing FRET biosensors have previously detected that γ-secretase processes APP C99 primarily in late endosomes and lysosomes in live/intact neurons. Moreover we have shown that Aβ peptides are enriched in the same subcellular loci. Given that γ-secretase is integrated into the membrane bilayer and functionally links to lipid membrane properties in vitro, it is presumable that γ-secretase function correlates with endosome and lysosome membrane properties in live/intact cells. In the present study, we show using unique live-cell imaging and biochemical assays that the endo-lysosomal membrane in primary neurons is more disordered and, as a result, more permeable than in CHO cells. Interestingly, γ-secretase processivity is decreased in primary neurons, resulting in the predominant production of long Aβ42 instead of short Aβ38. In contrast, CHO cells favor Aβ38 over the Aβ42 generation. Our findings are consistent with the previous in vitro studies, demonstrating the functional interaction between lipid membrane properties and γ-secretase and provide further evidence that γ-secretase acts in late endosomes and lysosomes in live/intact cells.
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spelling pubmed-100076192023-03-12 Endosome and Lysosome Membrane Properties Functionally Link to γ-Secretase in Live/Intact Cells Houser, Mei C. Q. Mitchell, Shane P. C. Sinha, Priyanka Lundin, Brianna Berezovska, Oksana Maesako, Masato Sensors (Basel) Article Our unique multiplexed imaging assays employing FRET biosensors have previously detected that γ-secretase processes APP C99 primarily in late endosomes and lysosomes in live/intact neurons. Moreover we have shown that Aβ peptides are enriched in the same subcellular loci. Given that γ-secretase is integrated into the membrane bilayer and functionally links to lipid membrane properties in vitro, it is presumable that γ-secretase function correlates with endosome and lysosome membrane properties in live/intact cells. In the present study, we show using unique live-cell imaging and biochemical assays that the endo-lysosomal membrane in primary neurons is more disordered and, as a result, more permeable than in CHO cells. Interestingly, γ-secretase processivity is decreased in primary neurons, resulting in the predominant production of long Aβ42 instead of short Aβ38. In contrast, CHO cells favor Aβ38 over the Aβ42 generation. Our findings are consistent with the previous in vitro studies, demonstrating the functional interaction between lipid membrane properties and γ-secretase and provide further evidence that γ-secretase acts in late endosomes and lysosomes in live/intact cells. MDPI 2023-02-28 /pmc/articles/PMC10007619/ /pubmed/36904854 http://dx.doi.org/10.3390/s23052651 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Houser, Mei C. Q.
Mitchell, Shane P. C.
Sinha, Priyanka
Lundin, Brianna
Berezovska, Oksana
Maesako, Masato
Endosome and Lysosome Membrane Properties Functionally Link to γ-Secretase in Live/Intact Cells
title Endosome and Lysosome Membrane Properties Functionally Link to γ-Secretase in Live/Intact Cells
title_full Endosome and Lysosome Membrane Properties Functionally Link to γ-Secretase in Live/Intact Cells
title_fullStr Endosome and Lysosome Membrane Properties Functionally Link to γ-Secretase in Live/Intact Cells
title_full_unstemmed Endosome and Lysosome Membrane Properties Functionally Link to γ-Secretase in Live/Intact Cells
title_short Endosome and Lysosome Membrane Properties Functionally Link to γ-Secretase in Live/Intact Cells
title_sort endosome and lysosome membrane properties functionally link to γ-secretase in live/intact cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10007619/
https://www.ncbi.nlm.nih.gov/pubmed/36904854
http://dx.doi.org/10.3390/s23052651
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