Amyloid precursor protein controls cholesterol turnover needed for neuronal activity

Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regula...

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Main Authors:	Pierrot, Nathalie, Tyteca, Donatienne, D'auria, Ludovic, Dewachter, Ilse, Gailly, Philippe, Hendrickx, Aurélie, Tasiaux, Bernadette, Haylani, Laetitia El, Muls, Nathalie, N'Kuli, Francisca, Laquerrière, Annie, Demoulin, Jean-Baptiste, Campion, Dominique, Brion, Jean-Pierre, Courtoy, Pierre J, Kienlen-Campard, Pascal, Octave, Jean-Noël
Format:	Online
Language:	English
Published:	WILEY-VCH Verlag 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628100/

id	pubmed-3628100
recordtype	oai_dc
spelling	pubmed-36281002013-04-19 Amyloid precursor protein controls cholesterol turnover needed for neuronal activity Pierrot, Nathalie Tyteca, Donatienne D'auria, Ludovic Dewachter, Ilse Gailly, Philippe Hendrickx, Aurélie Tasiaux, Bernadette Haylani, Laetitia El Muls, Nathalie N'Kuli, Francisca Laquerrière, Annie Demoulin, Jean-Baptiste Campion, Dominique Brion, Jean-Pierre Courtoy, Pierre J Kienlen-Campard, Pascal Octave, Jean-Noël Research Articles Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full-length APP expression affected neuronal lipid metabolism. Expression of APP decreased HMG-CoA reductase (HMGCR)-mediated cholesterol biosynthesis and SREBP mRNA levels, while its down regulation had opposite effects. APP and SREBP1 co-immunoprecipitated and co-localized in the Golgi. This interaction prevented Site-2 protease-mediated processing of SREBP1, leading to inhibition of transcription of its target genes. A GXXXG motif in APP sequence was critical for regulation of HMGCR expression. In astrocytes, APP and SREBP1 did not interact nor did APP affect cholesterol biosynthesis. Neuronal expression of APP decreased both HMGCR and cholesterol 24-hydroxylase mRNA levels and consequently cholesterol turnover, leading to inhibition of neuronal activity, which was rescued by geranylgeraniol, generated in the mevalonate pathway, in both APP expressing and mevastatin treated neurons. We conclude that APP controls cholesterol turnover needed for neuronal activity. WILEY-VCH Verlag 2013-04 2013-04-02 /pmc/articles/PMC3628100/ /pubmed/23554170 http://dx.doi.org/10.1002/emmm.201202215 Text en Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO http://creativecommons.org/licenses/by/2.5/ This is an open access article under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Pierrot, Nathalie Tyteca, Donatienne D'auria, Ludovic Dewachter, Ilse Gailly, Philippe Hendrickx, Aurélie Tasiaux, Bernadette Haylani, Laetitia El Muls, Nathalie N'Kuli, Francisca Laquerrière, Annie Demoulin, Jean-Baptiste Campion, Dominique Brion, Jean-Pierre Courtoy, Pierre J Kienlen-Campard, Pascal Octave, Jean-Noël
spellingShingle	Pierrot, Nathalie Tyteca, Donatienne D'auria, Ludovic Dewachter, Ilse Gailly, Philippe Hendrickx, Aurélie Tasiaux, Bernadette Haylani, Laetitia El Muls, Nathalie N'Kuli, Francisca Laquerrière, Annie Demoulin, Jean-Baptiste Campion, Dominique Brion, Jean-Pierre Courtoy, Pierre J Kienlen-Campard, Pascal Octave, Jean-Noël Amyloid precursor protein controls cholesterol turnover needed for neuronal activity
author_facet	Pierrot, Nathalie Tyteca, Donatienne D'auria, Ludovic Dewachter, Ilse Gailly, Philippe Hendrickx, Aurélie Tasiaux, Bernadette Haylani, Laetitia El Muls, Nathalie N'Kuli, Francisca Laquerrière, Annie Demoulin, Jean-Baptiste Campion, Dominique Brion, Jean-Pierre Courtoy, Pierre J Kienlen-Campard, Pascal Octave, Jean-Noël
author_sort	Pierrot, Nathalie
title	Amyloid precursor protein controls cholesterol turnover needed for neuronal activity
title_short	Amyloid precursor protein controls cholesterol turnover needed for neuronal activity
title_full	Amyloid precursor protein controls cholesterol turnover needed for neuronal activity
title_fullStr	Amyloid precursor protein controls cholesterol turnover needed for neuronal activity
title_full_unstemmed	Amyloid precursor protein controls cholesterol turnover needed for neuronal activity
title_sort	amyloid precursor protein controls cholesterol turnover needed for neuronal activity
description	Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full-length APP expression affected neuronal lipid metabolism. Expression of APP decreased HMG-CoA reductase (HMGCR)-mediated cholesterol biosynthesis and SREBP mRNA levels, while its down regulation had opposite effects. APP and SREBP1 co-immunoprecipitated and co-localized in the Golgi. This interaction prevented Site-2 protease-mediated processing of SREBP1, leading to inhibition of transcription of its target genes. A GXXXG motif in APP sequence was critical for regulation of HMGCR expression. In astrocytes, APP and SREBP1 did not interact nor did APP affect cholesterol biosynthesis. Neuronal expression of APP decreased both HMGCR and cholesterol 24-hydroxylase mRNA levels and consequently cholesterol turnover, leading to inhibition of neuronal activity, which was rescued by geranylgeraniol, generated in the mevalonate pathway, in both APP expressing and mevastatin treated neurons. We conclude that APP controls cholesterol turnover needed for neuronal activity.
publisher	WILEY-VCH Verlag
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628100/
_version_	1611970524349464576

Amyloid precursor protein controls cholesterol turnover needed for neuronal activity

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