Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity.
JCI Insight
; 6(16)2021 08 23.
Article
de En
| MEDLINE
| ID: mdl-34228639
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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Cortex cérébral
/
Précurseur de la protéine bêta-amyloïde
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Récepteur PPAR alpha
/
Maladie d'Alzheimer
Type d'étude:
Observational_studies
/
Risk_factors_studies
Limites:
Aged
/
Aged80
/
Animals
/
Female
/
Humans
/
Male
Langue:
En
Journal:
JCI Insight
Année:
2021
Type de document:
Article