Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes

Dolores Del Prete; Jan M. Suski; Bénédicte Oulès; Delphine Debayle; Anne Sophie Gay; Sandra Lacas-Gervais; Renaud Bussiere; Charlotte Bauer; Paolo Pinton; Patrizia Paterlini-Bréchot; Mariusz R. Wieckowski; Frédéric Checler; Mounia Chami

doi:10.3233/JAD-160953

Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes

Dolores Del Prete, Jan M. Suski, Bénédicte Oulès, Delphine Debayle, Anne Sophie Gay, Sandra Lacas-Gervais, Renaud Bussiere, Charlotte Bauer, Paolo Pinton, Patrizia Paterlini-Bréchot, Mariusz R. Wieckowski, Frédéric Checler, Mounia Chami^*

^*Corresponding author for this work

Centre for Stem Cells & Regenerative Medicine

Research output: Contribution to journal › Article › peer-review

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Abstract

Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-β protein precursor (AβPP) and its proteolytic products in MAMs. We reveal that AβPP and its catabolites are present in MAMs in cellular models overexpressing wild type AβPP or AβPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both β- and γ-secretases are present and harbor AβPP processing activities in MAMs. Interestingly, cells overexpressing APP_swe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aβ production and reversed by inhibiting β- or γ-secretases. Using a proteomic approach, we show that AβPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AβPP processing and proteomic interactome in MAMs deregulation taking place in AD.

Original language	English
Pages (from-to)	1549-1570
Number of pages	22
Journal	JOURNAL OF ALZHEIMERS DISEASE
Volume	55
Issue number	4
Early online date	20 Dec 2016
DOIs	https://doi.org/10.3233/JAD-160953
Publication status	E-pub ahead of print - 20 Dec 2016

Keywords

Alzheimer disease
amyloid-β protein precursor
lipids
mitochondria associated membranes
proteomic

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3233/JAD-160953

Localization and Processing of_DEL PRETE_Publishedonline20December2016_GOLD VoR (CC BY)Final published version, 2.34 MB

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Del Prete, D., Suski, J. M., Oulès, B., Debayle, D., Gay, A. S., Lacas-Gervais, S., Bussiere, R., Bauer, C., Pinton, P., Paterlini-Bréchot, P., Wieckowski, M. R., Checler, F., & Chami, M. (2016). Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes. JOURNAL OF ALZHEIMERS DISEASE, 55(4), 1549-1570. Advance online publication. https://doi.org/10.3233/JAD-160953

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abstract = "Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-β protein precursor (AβPP) and its proteolytic products in MAMs. We reveal that AβPP and its catabolites are present in MAMs in cellular models overexpressing wild type AβPP or AβPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both β- and γ-secretases are present and harbor AβPP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aβ production and reversed by inhibiting β- or γ-secretases. Using a proteomic approach, we show that AβPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AβPP processing and proteomic interactome in MAMs deregulation taking place in AD.",

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author = "{Del Prete}, Dolores and Suski, {Jan M.} and B{\'e}n{\'e}dicte Oul{\`e}s and Delphine Debayle and Gay, {Anne Sophie} and Sandra Lacas-Gervais and Renaud Bussiere and Charlotte Bauer and Paolo Pinton and Patrizia Paterlini-Br{\'e}chot and Wieckowski, {Mariusz R.} and Fr{\'e}d{\'e}ric Checler and Mounia Chami",

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Del Prete, D, Suski, JM, Oulès, B, Debayle, D, Gay, AS, Lacas-Gervais, S, Bussiere, R, Bauer, C, Pinton, P, Paterlini-Bréchot, P, Wieckowski, MR, Checler, F & Chami, M 2016, 'Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes', JOURNAL OF ALZHEIMERS DISEASE, vol. 55, no. 4, pp. 1549-1570. https://doi.org/10.3233/JAD-160953

TY - JOUR

T1 - Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes

AU - Del Prete, Dolores

AU - Suski, Jan M.

AU - Oulès, Bénédicte

AU - Debayle, Delphine

AU - Gay, Anne Sophie

AU - Lacas-Gervais, Sandra

AU - Bussiere, Renaud

AU - Bauer, Charlotte

AU - Pinton, Paolo

AU - Paterlini-Bréchot, Patrizia

AU - Wieckowski, Mariusz R.

AU - Checler, Frédéric

AU - Chami, Mounia

PY - 2016/12/20

Y1 - 2016/12/20

N2 - Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-β protein precursor (AβPP) and its proteolytic products in MAMs. We reveal that AβPP and its catabolites are present in MAMs in cellular models overexpressing wild type AβPP or AβPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both β- and γ-secretases are present and harbor AβPP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aβ production and reversed by inhibiting β- or γ-secretases. Using a proteomic approach, we show that AβPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AβPP processing and proteomic interactome in MAMs deregulation taking place in AD.

AB - Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-β protein precursor (AβPP) and its proteolytic products in MAMs. We reveal that AβPP and its catabolites are present in MAMs in cellular models overexpressing wild type AβPP or AβPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both β- and γ-secretases are present and harbor AβPP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aβ production and reversed by inhibiting β- or γ-secretases. Using a proteomic approach, we show that AβPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AβPP processing and proteomic interactome in MAMs deregulation taking place in AD.

KW - Alzheimer disease

KW - amyloid-β protein precursor

KW - lipids

KW - mitochondria associated membranes

KW - proteomic

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DO - 10.3233/JAD-160953

M3 - Article

AN - SCOPUS:85007236814

SN - 1387-2877

VL - 55

SP - 1549

EP - 1570

JO - JOURNAL OF ALZHEIMERS DISEASE

JF - JOURNAL OF ALZHEIMERS DISEASE

IS - 4

ER -

Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes

Abstract

Keywords

UN SDGs

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