Abstract
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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in the elderly population
These Apolipoprotein E (apoE)-related pathways could be interdependently or independently involved in the pathogenesis of AD as well as cognitive function [2,3]. Though it remains unclear how apoE is involved in the pathogenesis of AD, it is of note that the levels of apoE4 are lower than those of apoE3 in the brain of apoE-targeted replacement (TR) mice expressing each of the human apoE isoforms under the control of the endogenous mouse promoter, and in the plasma and cerebrospinal fluid of humans with APOE3 or APOE4 [4,5,6,7]
The effects of OS in these primary astrocytes were observed at one order of magnitude lower than that needed for immortalized cells, suggesting more potent effects to increase apoE secretion in vivo
Summary
Alzheimer’s disease (AD) is the most common form of dementia in the elderly population. ApoE plays important roles in neuroinflammation and metabolism of amyloid-β (Aβ). These apoE-related pathways could be interdependently or independently involved in the pathogenesis of AD as well as cognitive function [2,3]. Up-regulation of apoE secretion and lipidation status could be an attractive pharmacological approach for AD therapy. Despite these promises, the potential clinical applications of these compounds are debated due to their intrinsic side effects [12,13]
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