Research: ZAO and COLLEAGUES,

Listed in Issue 221

Abstract

ZAO and COLLEAGUES,  From the Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200032, China performed a drug screen for compounds which modulate Apolipoprotein E (apoE), the brain’s major cholesterol transport protein, exploring potential drugs for Alzheimer’s disease (AD).

Background

Apolipoprotein E (apoE) is the major cholesterol transport protein in the brain. Among the three human APOE alleles (APOE2, APOE3, and APOE4), APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease (AD). The accumulation of amyloid-β (Aβ) is a central event in AD pathogenesis. Increasing evidence demonstrates that apoE isoforms differentially regulate AD-related pathways through both Aβ-dependent and -independent mechanisms; therefore, modulating apoE secretion, lipidation, and function might be an attractive approach for AD therapy.

Methodology

The authors performed a drug screen for compounds that modulate apoE production in immortalized astrocytes derived from apoE3-targeted replacement mice.

Results

Here, the authors report that retinoic acid (RA) isomers, including all-trans-RA, 9-cis-RA, and 13-cis-RA, significantly increase apoE secretion to ~4-fold of control through retinoid X receptor (RXR) and RA receptor. These effects on modulating apoE are comparable with the effects recently reported for the RXR agonist bexarotene. Furthermore, all of these compounds increased the expression of the cholesterol transporter ABCA1 and ABCG1 levels and decreased cellular uptake of Aβ in an apoE-dependent manner. Both bexarotene and 9-cis-RA promote the lipidation status of apoE, in which 9-cis-RA promotes a stronger effect and exhibits less cytotoxicity compared with bexarotene. Importantly, this research showed that oral administration of bexarotene and 9-cis-RA significantly increases apoE, ABCA1, and ABCG1 levels in mouse brains.

Conclusion

Taken together, the results demonstrate that RXR/RA receptor agonists, including several RA isomers, are effective modulators of apoE secretion and lipidation and may be explored as potential drugs for AD therapy.

References

Zhao J, Fu Y, Liu CC, Shinohara M, Nielsen HM, Dong Q, Kanekiyo T and Bu G. Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the retinoid X receptor/retinoic acid receptor pathway. J Biol Chem. 18;289(16):11282-92. doi: 10.1074/jbc.M113.526095. Epub 2014 Mar 5. Apr 2014.

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