Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity
Francisco Sáez-Orellana, … , Jean-Noël Octave, Nathalie Pierrot
Francisco Sáez-Orellana, … , Jean-Noël Octave, Nathalie Pierrot
Published July 6, 2021
Citation Information: JCI Insight. 2021;6(16):e150099. https://doi.org/10.1172/jci.insight.150099.
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Research Article Neuroscience

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

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.

Authors

Francisco Sáez-Orellana, Thomas Leroy, Floriane Ribeiro, Anna Kreis, Karelle Leroy, Fanny Lalloyer, Eric Baugé, Bart Staels, Charles Duyckaerts, Jean-Pierre Brion, Philippe Gailly, Jean-Noël Octave, Nathalie Pierrot

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Figure 2

Human APP expression decreases Ppara expression and PPARα downstream target genes in old mice.

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Human APP expression decreases Ppara expression and PPARα downstream tar...
Brain frontal cortex tissues from transgenic mice overexpressing nonmutated human APP (hAPPWT) and WT littermates were analyzed at 3–4, 6–8, and 11–12 months old (mo). (A) The expression of hAPP was investigated in mice brain lysates (n = 6 of each) by immunoblot analysis (see complete unedited blots in the supplemental material) with the specific WO2 antibody recognizing hAPP and anti-APP C-terminal antibody recognizing both hAPP and endogenous APP (APP). Blots were further probed using anti–α-tubulin antibody. (B) Relative density of APP expression was compared with α-tubulin. Results were normalized compared with 3–4 mo WT and are shown as mean ± SEM. A Kruskal-Wallis test followed by Dunn’s multiple comparisons posttest was used to assess significance of the mean (APP expression at 3–4, 6–8, and 11–12 mo, P < 0.05). (C–F) Quantitative real-time PCR analyses (n = 7 of each) for Ppara, Acox1, Cpt1a, and Pdk4 mRNA levels. Results were normalized to Rpl32 mRNA, compared with 3–4 mo WT, and shown as mean ± SEM. A Kruskal-Wallis test followed by Dunn’s multiple comparisons posttest was used to assess significance of the mean (11–12 mo hAPPWT mice: Ppara mRNA, P = 0.012, Acox1 mRNA, P = 0.0008, Cpt1a mRNA, P = 0.031; Pdk4 mRNA, P = 0.022), *P < 0.05, ***P < 0.001.