Science Translational Medicine 2015-11-18

The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis.

Jinkuk Choi, Jie Gao, Jaekwang Kim, Cynthia Hong, Jungsu Kim, Peter Tontonoz

Index: Sci. Transl. Med. 7 , 314ra184, (2015)

Full Text: HTML

Abstract

Apolipoprotein E (ApoE) is an important modifier of Alzheimer's disease (AD) pathogenesis, and its abundance has been linked to the clearance of β-amyloid (Aβ) in the brain. The pathways that control the clearance of ApoE in the brain are incompletely understood. We report that Idol, an E3 ubiquitin ligase that targets the low-density lipoprotein receptor (LDLR) for degradation, is a critical determinant of brain ApoE metabolism and Aβ plaque biogenesis. Previous work has shown that Idol contributes minimally to the regulation of hepatic LDLR expression in mice. By contrast, we demonstrate that Idol is a primary physiological regulator of LDLR protein in the brain, controlling the clearance of both ApoE-containing high-density lipoprotein (HDL) particles and Aβ. We studied the consequences of loss of Idol expression in a transgenic mouse model of Aβ amyloidosis. Idol deficiency increased brain LDLR, decreased ApoE, decreased soluble and insoluble Aβ, reduced amyloid plaque burden, and ameliorated neuroinflammation. These findings identify Idol as a gatekeeper of LDLR-dependent ApoE and Aβ clearance in the brain and a potential enzyme target for therapeutic intervention in AD. Copyright © 2015, American Association for the Advancement of Science.


Related Compounds

  • sodium chloride
  • Ethanol
  • sodium dodecyl sul...
  • Bis-tris methane
  • Deoxycholic acid
  • SODIUM CHLOR...
  • DL-Glyceraldehyde...
  • 4',6-Diamidino-2-p...
  • Thioflavine S
  • Ethylenediaminetet...

Related Articles:

Salicylic acid signaling controls the maturation and localization of the arabidopsis defense protein ACCELERATED CELL DEATH6.

2014-08-01

[Mol. Plant 7(8) , 1365-83, (2014)]

Mechanism of human PTEN localization revealed by heterologous expression in Dictyostelium.

2014-12-11

[Oncogene 33(50) , 5688-96, (2014)]

Functional consequence of the MET-T1010I polymorphism in breast cancer.

2015-02-20

[Oncotarget 6(5) , 2604-14, (2015)]

Aptamer-based polyvalent ligands for regulated cell attachment on the hydrogel surface.

2015-04-13

[Biomacromolecules 16(4) , 1382-9, (2015)]

Melatonin-mediated Bim up-regulation and cyclooxygenase-2 (COX-2) down-regulation enhances tunicamycin-induced apoptosis in MDA-MB-231 cells.

2015-04-01

[J. Pineal Res. 58(3) , 310-20, (2015)]

More Articles...