PPAR-α Agonist GW7647 Protects Against Oxidative Stress and Iron Deposit via GPx4 in a Transgenic Mouse Model of Alzheimer's Diseases

Alzheimer's disease (AD) is a neurodegenerative disease caused by lipid peroxidation and iron hemostasis of the brain. PPAR-α is regarded as the most encouraging therapeutic approach of several neurodegenerative and metabolic disorders, due to its potent regulatory effects. In this study, we examined the ameliorative effect and the mechanisms of a PPAR-α agonist, GW7647, on the established AD models using APP/PS1 mice and APPsw/SH-SY5Y cells. Through Aβ quantification and behavioral test, we found that GW7647 reduced Aβ burden and improved cognitive defect in APP/PS1 mice. Liquid chromatography-mass spectrometry analysis indicated that GW7647 could enter the brain after oral administration. Neuronal cell death and iron deposit were inhibited, accompanied by decreased lipid peroxidation and inflammation. In an in vitro study of APPsw cells, we found that PPAR-α directly bound with GPx4 intron3 to promote GPx4 transcription and reduced the iron transport capability. Our data suggested that activation of PPAR-α by GW7647 improved the disruption of iron homeostasis in the brain of APP/PS1 mice and alleviated neuronal inflammation and lipid peroxidation, which was possibly related to the upregulated transcription of GPx4 mediated by the interaction of GPx4 noncoding region and the PPAR-α.

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:13

Enthalten in:

ACS chemical neuroscience - 13(2022), 2 vom: 19. Jan., Seite 207-216

Sprache:

Englisch

Beteiligte Personen:

Qu, Xiao-Xia [VerfasserIn]
He, Jia-Huan [VerfasserIn]
Cui, Zhi-Qiang [VerfasserIn]
Yang, Tuo [VerfasserIn]
Sun, Xiao-Hong [VerfasserIn]

Links:

Volltext

Themen:

Alzheimer’s diseases
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Butyrates
E1UOL152H7
GPx4
GW 7647
Iron
Iron deposit
Journal Article
Oxidative stress
PPAR-α
Peroxisome Proliferator-Activated Receptors
Phenylurea Compounds
Presenilin-1
Research Support, Non-U.S. Gov't

Anmerkungen:

Date Completed 27.01.2022

Date Revised 27.01.2022

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1021/acschemneuro.1c00516

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM335015409