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2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer’s Disease

There is currently no effective treatment against Alzheimer’s disease (AD), although many strategies have been applied to reduce beta-amyloid (Aβ) levels. Here, we investigated 2,4-diacetylphloroglucinol (DAPG) effects on Aβ levels and mechanisms of action. DAPG was the most effective phloroglucinol...

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Autores principales: Jang, Bong-Geum, Choi, Boyoung, Kim, Suyeon, Lee, Duk-Shin, Lee, Jisun, Koh, Young Ho, Jo, Sangmee Ahn, Kim, Ji-Eun, Kang, Tae-Cheon, Kim, Min-Ju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9406471/
https://www.ncbi.nlm.nih.gov/pubmed/36010661
http://dx.doi.org/10.3390/cells11162585
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author Jang, Bong-Geum
Choi, Boyoung
Kim, Suyeon
Lee, Duk-Shin
Lee, Jisun
Koh, Young Ho
Jo, Sangmee Ahn
Kim, Ji-Eun
Kang, Tae-Cheon
Kim, Min-Ju
author_facet Jang, Bong-Geum
Choi, Boyoung
Kim, Suyeon
Lee, Duk-Shin
Lee, Jisun
Koh, Young Ho
Jo, Sangmee Ahn
Kim, Ji-Eun
Kang, Tae-Cheon
Kim, Min-Ju
author_sort Jang, Bong-Geum
collection PubMed
description There is currently no effective treatment against Alzheimer’s disease (AD), although many strategies have been applied to reduce beta-amyloid (Aβ) levels. Here, we investigated 2,4-diacetylphloroglucinol (DAPG) effects on Aβ levels and mechanisms of action. DAPG was the most effective phloroglucinol derivative for reducing Aβ levels, without being toxic, in various models including HEK293 cells overexpressing Swedish mutant amyloid precursor protein (APP) (293sw), primary astrocytes isolated from APPsw/PS1dE9 transgenic mice, and after intrahippocampal injection of DAPG in APPsw/PS1dE9 transgenic mice. DAPG-mediated Aβ reduction was associated with increased soluble APPα (sAPPα) levels mediated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) but not ADAM17. ADAM10 inhibition in DAPG-treated cells prevented the effects on sAPPα but only partly on intracellular and secreted Aβ. To identify regulators of sAPPα and Aβ secretion, various inhibitors of intracellular trafficking were administered with DAPG. Brefeldin A (BFA) reversed DAPG-mediated changes in Aβ secretion in 293sw cells, whereas golgicide A (GCA) and BFA were effective in primary astrocytes, indicating a cell type-specific regulation of the trafficking. Moreover, GCA or BFA effects on sAPPα, but not Aβ, levels in primary astrocytes resembled those of ADAM10 inhibition, indicating at least partly independent trafficking pathways for sAPPα and Aβ. In conclusion, DAPG might be a promising drug candidate against AD regulating ADAM10 and intracellular trafficking, but optimizing DAPG ability to cross the BBB will be needed.
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spelling pubmed-94064712022-08-26 2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer’s Disease Jang, Bong-Geum Choi, Boyoung Kim, Suyeon Lee, Duk-Shin Lee, Jisun Koh, Young Ho Jo, Sangmee Ahn Kim, Ji-Eun Kang, Tae-Cheon Kim, Min-Ju Cells Article There is currently no effective treatment against Alzheimer’s disease (AD), although many strategies have been applied to reduce beta-amyloid (Aβ) levels. Here, we investigated 2,4-diacetylphloroglucinol (DAPG) effects on Aβ levels and mechanisms of action. DAPG was the most effective phloroglucinol derivative for reducing Aβ levels, without being toxic, in various models including HEK293 cells overexpressing Swedish mutant amyloid precursor protein (APP) (293sw), primary astrocytes isolated from APPsw/PS1dE9 transgenic mice, and after intrahippocampal injection of DAPG in APPsw/PS1dE9 transgenic mice. DAPG-mediated Aβ reduction was associated with increased soluble APPα (sAPPα) levels mediated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) but not ADAM17. ADAM10 inhibition in DAPG-treated cells prevented the effects on sAPPα but only partly on intracellular and secreted Aβ. To identify regulators of sAPPα and Aβ secretion, various inhibitors of intracellular trafficking were administered with DAPG. Brefeldin A (BFA) reversed DAPG-mediated changes in Aβ secretion in 293sw cells, whereas golgicide A (GCA) and BFA were effective in primary astrocytes, indicating a cell type-specific regulation of the trafficking. Moreover, GCA or BFA effects on sAPPα, but not Aβ, levels in primary astrocytes resembled those of ADAM10 inhibition, indicating at least partly independent trafficking pathways for sAPPα and Aβ. In conclusion, DAPG might be a promising drug candidate against AD regulating ADAM10 and intracellular trafficking, but optimizing DAPG ability to cross the BBB will be needed. MDPI 2022-08-19 /pmc/articles/PMC9406471/ /pubmed/36010661 http://dx.doi.org/10.3390/cells11162585 Text en © 2022 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
Jang, Bong-Geum
Choi, Boyoung
Kim, Suyeon
Lee, Duk-Shin
Lee, Jisun
Koh, Young Ho
Jo, Sangmee Ahn
Kim, Ji-Eun
Kang, Tae-Cheon
Kim, Min-Ju
2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer’s Disease
title 2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer’s Disease
title_full 2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer’s Disease
title_fullStr 2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer’s Disease
title_full_unstemmed 2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer’s Disease
title_short 2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer’s Disease
title_sort 2,4-diacetylphloroglucinol reduces beta-amyloid production and secretion by regulating adam10 and intracellular trafficking in cellular and animal models of alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9406471/
https://www.ncbi.nlm.nih.gov/pubmed/36010661
http://dx.doi.org/10.3390/cells11162585
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