1. Regulation of PPARα by APP in Alzheimer disease impacts the pharmacological modulation of synaptic activity
- Author
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Philippe Gailly, Anna Kreis, Karelle Leroy, Bart Staels, Nathalie Pierrot, Jean Pierre Brion, Francisco Saez-Orellana, Eric Bauge, Charles Duyckaerts, Jean-Noël Octave, Floriane Ribeiro, Thomas Leroy, Fanny Lalloyer, Université Catholique de Louvain = Catholic University of Louvain (UCL), Université libre de Bruxelles (ULB), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Belgian Fonds pour la Recherche Scientifique, The Concerted Research Actions, The Belgian Fonds de la Recherche Scientifique Médicale, the Queen Elisabeth Medical Foundation and the Fondation pour la Recherche sur la Maladie d’Alzheimer., Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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Male ,Regulator ,Research & Experimental Medicine ,Mouse models ,Amyloid beta-Protein Precursor ,0302 clinical medicine ,Gene Duplication ,Amyloid precursor protein ,DOWN-SYNDROME ,BRAIN ,Receptor ,Aged, 80 and over ,Cerebral Cortex ,Neurons ,0303 health sciences ,biology ,General Medicine ,MOUSE MODEL ,Sciences bio-médicales et agricoles ,3. Good health ,Cell biology ,Medicine, Research & Experimental ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Alzheimer's disease ,Alzheimer disease ,Life Sciences & Biomedicine ,Research Article ,Genetically modified mouse ,BETA ,Mice, Transgenic ,METABOLISM ,Cell Line ,03 medical and health sciences ,Alzheimer Disease ,Genetic predisposition ,medicine ,Animals ,Humans ,PPAR alpha ,030304 developmental biology ,Aged ,Science & Technology ,Lipogenesis ,Physiologie pathologique ,Médecine pathologie humaine ,Lipid metabolism ,Généralités ,medicine.disease ,GENE ,DUPLICATION ,POLYMORPHISM ,MICE ,Disease Models, Animal ,Gene Expression Regulation ,Case-Control Studies ,Synaptic plasticity ,Synapses ,biology.protein ,OVEREXPRESSION ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Among genetic susceptibility loci associated with late-onset Alzheimer disease (LOAD), genetic polymorphisms identified in genes encoding lipid carriers led to the hypothesis that a disruption of lipid metabolism could promote disease progression. We previously reported that amyloid precursor protein (APP) involved in Alzheimer disease (AD) physiopathology impairs lipid synthesis needed for cortical networks' activity and that activation of peroxisome proliferator-activated receptor α (PPARα), a metabolic regulator involved in lipid metabolism, improves synaptic plasticity in an AD mouse model. These observations led us to investigate a possible correlation between PPARα function and full-length APP expression. Here, we report that PPARα expression and activation were inversely related to APP expression both in LOAD brains and in early-onset AD cases with a duplication of the APP gene, but not in control human brains. Moreover, human APP expression decreased PPARA expression and its related target genes in transgenic mice and in cultured cortical cells, while opposite results were observed in APP-silenced cortical networks. In cultured neurons, APP-mediated decrease or increase in synaptic activity was corrected by a PPARα-specific agonist and antagonist, respectively. APP-mediated control of synaptic activity was abolished following PPARα deficiency, indicating a key function of PPARα in this process., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2021
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