Regulation of PPAR alpha by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity

Saez-Orellana, Francisco; Leroy, Thomas; Ribeiro, Floriane; Kreis, Anna; Leroy, Karelle; Lalloyer, Fanny; Bauge, Eric; Staels, Bart; Duyckaerts, Charles; Brion, Jean-Pierre; Gailly, Philippe; Octave, Jean-Noel; Pierrot, Nathalie


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 alpha (PPAR alpha), 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 PPAR alpha function and full-length APP expression. Here, we report that PPAR alpha 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 PPAR alpha-specific agonist and antagonist, respectively. APP-mediated control of synaptic activity was abolished following PPAR alpha deficiency, indicating a key function of PPAR alpha in this process.

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Título según WOS: ID WOS:000689486700009 Not found in local WOS DB
Título de la Revista: JCI INSIGHT
Volumen: 6
Número: 16
Fecha de publicación: 2021


Notas: ISI