Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity
Open accessAbstract
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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miR-21 targets phosphatase and tensin homolog (PTEN).
“miR-21 was shown to target peroxisome proliferator-activated receptor alpha (PPARα) [73] and phosphatase and tensin homolog (PTEN) [74,75], among others.”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [74]
In the citing sentence, this source is cited as [73] for miR-21 targeting PPARα; the PTEN claim is attached to [74,75], not this source. The Results and Discussion passages describe APP-mediated regulation of PPARα, but searches for miR-21 and PTEN found no passage linking miR-21 to either target in our copy. (LLM, conf=0.76)
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- Authors
- Sáez-Orellana, F., 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.
- Affiliations
- UCLouvain (BE)
- Université Libre de Bruxelles (BE)
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Pierrot, Nathalie
- ORCID
- Venue
- JCI Insight
- Published
- 2021-08-23
- Volume
- 6
- Issue
- 16
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC8410016
- OpenAlex
- W3180304759
- Cited by
- 29
- References
- 88
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 14 · 2023: 6 · 2022: 3
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JCI Insight (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
- Lirias (submittedVersion, cc-by)
- HAL (submittedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
- Funders
- Fondation pour la Recherche sur la Maladie d’Alzheimer SAO-FRA (2017/002)
- Fondation Médicale Reine Elisabeth FMRE-GSKE (€ 180.000,2020-2022)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid precursor protein, PPARα, lipid metabolism, synaptic plasticity, early-onset Alzheimer's disease, late-onset Alzheimer's disease, cortical neurons, lipid carriers
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Cell Line, Cerebral Cortex, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Male, Mice, Transgenic, Neurons, Synapses, Case-Control Studies, Amyloid beta-Protein Precursor, Gene Duplication, PPAR alpha, Lipogenesis
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