title: Amyloid precursor protein controls cholesterol turnover needed for neuronal activity.
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.
authors.affiliation: Université Catholique de Louvain, Brussels, Belgium; Institute of Neuroscience, Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pierrot
authors.forename: Donatienne
authors.initials: D
authors.lastname: Tyteca
authors.forename: Ludovic
authors.initials: L
authors.lastname: D'auria
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
authors.forename: Philippe
authors.initials: P
authors.lastname: Gailly
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hendrickx
authors.forename: Bernadette
authors.initials: B
authors.lastname: Tasiaux
authors.forename: Laetitia El
authors.initials: LE
authors.lastname: Haylani
authors.forename: Nathalie
authors.initials: N
authors.lastname: Muls
authors.forename: Francisca
authors.initials: F
authors.lastname: N'kuli
authors.forename: Annie
authors.initials: A
authors.lastname: Laquerrière
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Brion
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Courtoy
authors.forename: Pascal
authors.initials: P
authors.lastname: Kienlen-Campard
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Octave
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases
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