Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity.
(2021) JCI Insight — Vol. 6, n° 16 (2021)
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Saez Orellana, Francisco Javier 
- 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.
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Saez Orellana, F. J., LEROY, T., Ribeiro, F., Kreis, A., Leroy, K., Lalloyer, F., Baugé, E., Staels, B., Duyckaerts, C., Brion, J.-P., Gailly, P., Octave, J.-N., & Pierrot, N. (2021). Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity. JCI Insight, 6(16). https://doi.org/10.1172/jci.insight.150099 (Original work published 2021)