Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity
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
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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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 5

Control of synaptic activity by APP in cortical cultures disappears in the absence of PPARα.

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Control of synaptic activity by APP in cortical cultures disappears in t...
Primary cultures of mouse cortical cells prepared from WT and Ppara-deficient (Ppara–/–) mice and infected with recombinant adenoviruses encoding hrGFP or hAPP proteins or with lentiviruses encoding a shRNA construct designed to target endogenous APP (shAPP) or a scrambled shRNA encoding GFP (shScra-GFP). (A) At 13–14 DIV, absence of PPARα expression in cultured cells was assessed by measuring Ppara mRNA levels by semiquantitative real-time PCR (RT-PCR). (B and C) Representative immunoblots of cell lysates, 3 independent experiments (the lanes were run on the same gel but were noncontiguous). The expression of hAPP was monitored with the specific WO2 antibody recognizing hAPP and anti-APP C-terminal antibody recognizing both hAPP and endogenous APP (APP). Immunoblots were further probed using anti-GFP and –α-tubulin antibodies. (D) APP expression/α-tubulin ratios (n = 4 of each) compared with hrGFP or shScra-GFP WT cells (mean ± SEM); 1-way ANOVA followed by Tukey’s multiple comparisons test (APP: WT and Ppara–/– hAPP P = 0.002; WT and Ppara–/– shAPP, P = 0.008 and P = 0.015, respectively). (E) RMP measured in WT and Ppara–/– transduced neurons (n = 11 cells per group analyzed in 3 independent experiments). (F) Representative traces of total synaptic activity and (G) mean values of synaptic events’ frequency (n = 8–11 cells per group analyzed in 3 independent experiments). (H) Cumulative probability plot of the amplitude distribution (n = 10–20 cells per group in 3 independent experiments) measured in WT and Ppara–/– transduced neurons. (E–H) Brown-Forsythe and Welch 1-way ANOVA tests followed by Dunnett’s T3 multiple comparisons test. *P < 0.05, **P < 0.01, and ns P > 0.05.