Journal Article

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

Guan, Pei-Pei, Wang, Zhan-You, Wang, Pu, Yang, Liu-Qing, Xu, Guo-Biao

2019

Overview

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.

• Publisher: Elsevier Inc,Springer International Publishing,Springer Nature B.V
• Subject: ABCA1 protein / Alzheimer's disease / Amyloid beta-Protein Precursor - genetics / Amyloid beta-Protein Precursor - metabolism / Amyloid precursor protein / Animals / ATP Binding Cassette Transporter 1 - metabolism / ATP-binding cassette subfamily A member 1 / ATP-binding protein / Biomedical and Life Sciences / Biomedicine / Cholesterol / Cholesterol - metabolism / Cognition - drug effects / Cognitive ability / Cognitive Dysfunction - drug therapy / Cognitive Dysfunction - metabolism / Fibrils / Intracellular signalling / Lipid metabolism / Mice / Mice, Transgenic / Monomers / Neurobiology / Neurodegenerative diseases / Neurology / Neuroprotection / Neurosciences / Neurosurgery / Next-generation sequencing / Original / Original Article / PPAR gamma - metabolism / Presenilin 1 / Presenilin 2 / presenilin enhancer protein 2 / Presenilin-1 - genetics / Presenilin-1 - metabolism / Prostaglandin A1 / Prostaglandins / Prostaglandins A - pharmacology / Prostaglandins A - therapeutic use / Proteins / Signal transduction / Signal Transduction - drug effects / Transgenic animals / Transgenic mice / β-Amyloid