Prostaglandin A1 Inhibits the Cognitive Decline of APP/PS1 Transgenic Mice via PPARγ/ABCA1-dependent Cholesterol Efflux Mechanisms.

Abstract

Prostaglandins (PGs) are early and key contributors to chronic neurodegenerative diseases. As one important member of classical PGs, PGA1 has been reported to exert potential neuroprotective effects. However, the mechanisms remain unknown. To this end, we are prompted to investigate whether PGA1 is a useful neurological treatment for Alzheimer's disease (AD) or not. Using high-throughput sequencing, we found that PGA1 potentially regulates cholesterol metabolism and lipid transport. Interestingly, we further found that short-term administration of PGA1 decreased the levels of the monomeric and oligomeric β-amyloid protein (oAβ) in a cholesterol-dependent manner. In detail, PGA1 activated the peroxisome proliferator-activated receptor-gamma (PPARγ) and ATP-binding cassette subfamily A member 1 (ABCA1) signalling pathways, promoting the efflux of cholesterol and decreasing the intracellular cholesterol levels. Through PPARγ/ABCA1/cholesterol-dependent pathway, PGA1 decreased the expression of presenilin enhancer protein 2 (PEN-2), which is responsible for the production of Aβ. More importantly, long-term administration of PGA1 remarkably decreased the formation of Aβ monomers, oligomers, and fibrils. The actions of PGA1 on the production and deposition of Aβ ultimately improved the cognitive decline of the amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice.

• Authors: Guo-Biao Xu, Liu-Qing Yang, Pei-Pei Guan, Zhan-You Wang, Pu Wang
• Journal: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (Neurotherapeutics) Vol. 16 Issue 2 Pg. 505-522 (04 2019) ISSN: 1878-7479 [Electronic] United States
• PMID: 30627958 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter 1
• Amyloid beta-Protein Precursor
• PPAR gamma
• Presenilin-1
• Prostaglandins A
• Cholesterol
• prostaglandin A1

Topics

• ATP Binding Cassette Transporter 1 (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Cholesterol (metabolism)
• Cognition (drug effects)
• Cognitive Dysfunction (drug therapy, metabolism)
• Mice
• Mice, Transgenic
• PPAR gamma (metabolism)
• Presenilin-1 (genetics, metabolism)
• Prostaglandins A (pharmacology, therapeutic use)
• Signal Transduction (drug effects)