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Title: | Amyloid precursor protein controls cholesterol turnover needed for neuronal activity | 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 |
Issue Date: | 2013 | Publisher: | WILEY | Source: | EMBO molecular medicine, 5 (4) , p. 608-25 -625 | Abstract: | 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. | Keywords: | Alzheimer's disease;calcium oscillations;cholesterol turnover;neuron;SREBP-1 | Document URI: | http://hdl.handle.net/1942/30298 | ISSN: | 1757-4676 | e-ISSN: | 1757-4684 | DOI: | 10.1002/emmm.201202215 | ISI #: | 000317070200012 | Rights: | 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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Pierrot_et_al-2013-EMBO_Molecular_Medicine.pdf | Published version | 1.37 MB | Adobe PDF | View/Open |
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