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

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

doi:10.1172/jci.insight.150099

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.

Highlights

Alzheimer disease (AD) is the most common form of dementia, accounting for nearly 70% of the cases worldwide [1]
Since lipid biochemistry is disrupted in AD [10, 26] and given that one of the main neuropathological characteristics involved in AD pathogenesis implicates the amyloid precursor protein (APP) [27, 28], which we have previously reported decreases both cholesterol and fatty acid (FA) biosynthesis when its expression level increases [23], we wondered whether modifications in PPARA expression observed could be related to human APP (hAPP) expression
While the global expression level of full-length hAPP was unchanged in late-onset Alzheimer disease (LOAD) compared with controls (Figure 1, D and E), a case-by-case analysis revealed a tight inverse correlation between hAPP and PPARA expressions in LOAD brains, but not in control brains (Figure 1, F and G), suggesting that PPARA expression is regulated by hAPP expression level only in LOAD

Summary

Introduction

Alzheimer disease (AD) is the most common form of dementia, accounting for nearly 70% of the cases worldwide [1]. Among the most important AD genetic risk factors, genetic polymorphisms found first in APOE and later in CLU and ABCA7 genes encoding lipid carriers [4] led to the hypothesis that a disruption of lipid metabolism could promote disease progression [5] This hypothesis is sustained by findings reporting that genetic polymorphisms in SREBF and PPARA genes, involved in cholesterol and fatty acid (FA) metabolism, were associated with an increased risk of LOAD [6,7,8], the association between the genetic polymorphism identified in PPARA encoding the peroxisome proliferator–activated receptor α (PPARα) and AD is controversial [9]. Inasmuch as PPARs’ expression is modified in AD brains [22], we hypothesized that the function of PPARα could be impaired in AD and may contribute to the progression of the disease

Methods

Results

Conclusion