Next Article in Journal
Plasma Rich in Growth Factors (PRGF) Disrupt the Blood-Brain Barrier Integrity and Elevate Amyloid Pathology in the Brains of 5XFAD Mice
Next Article in Special Issue
The Role of ApoE in HCV Infection and Comorbidity
Previous Article in Journal
Upregulated Autophagy in Calcific Aortic Valve Stenosis Confers Protection of Valvular Interstitial Cells
Previous Article in Special Issue
The Opposite Effect of c-Jun Transcription Factor on Apolipoprotein E Gene Regulation in Hepatocytes and Macrophages
Open AccessArticle

5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan
Neuroscience Graduate Program, Mayo Clinic, Jacksonville, FL 32224, USA
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1488;
Received: 12 February 2019 / Revised: 10 March 2019 / Accepted: 21 March 2019 / Published: 25 March 2019
Apolipoprotein E (apoE) is linked to the risk for Alzheimer’s disease (AD) and thus has been suggested to be an important therapeutic target. In our drug screening effort, we identified Ondansetron (OS), an FDA-approved 5-HT3 antagonist, as an apoE-modulating drug. OS at low micromolar concentrations significantly increased apoE secretion from immortalized astrocytes and primary astrocytes derived from apoE3 and apoE4-targeted replacement mice without generating cellular toxicity. Other 5-HT3 antagonists also had similar effects as OS, though their effects were milder and required higher concentrations. Antagonists for other 5-HT receptors did not increase apoE secretion. OS also increased mRNA and protein levels of the ATB-binding cassette protein A1 (ABCA1), which is involved in lipidation and secretion of apoE. Accordingly, OS increased high molecular weight apoE. Moreover, the liver X receptor (LXR) and ABCA1 antagonists blocked the OS-induced increase of apoE secretion, indicating that the LXR-ABCA1 pathway is involved in the OS-mediated facilitation of apoE secretion from astrocytes. The effects of OS on apoE and ABCA1 were also observed in human astrocytes derived from induced pluripotent stem cells (iPSC) carrying the APOE ε3/ε3 and APOE ε4/ε4 genotypes. Oral administration of OS at clinically-relevant doses affected apoE levels in the liver, though the effects in the brain were not observed. Collectively, though further studies are needed to probe its effects in vivo, OS could be a potential therapeutic drug for AD by modulating poE metabolism through the LXR-ABCA1 pathway. View Full-Text
Keywords: apoE; astrocytes; Alzheimer’s disease; ondansetron; LXR; ABCA1 apoE; astrocytes; Alzheimer’s disease; ondansetron; LXR; ABCA1
Show Figures

Figure 1

MDPI and ACS Style

Shinohara, M.; Shinohara, M.; Zhao, J.; Fu, Y.; Liu, C.-C.; Kanekiyo, T.; Bu, G. 5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway. Int. J. Mol. Sci. 2019, 20, 1488.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Search more from Scilit
Back to TopTop