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Sci. Transl. Med., 18 Nov 2015: Vol. 7, Issue 314, pp. 314ra184 | DOI: 10.1126/scitranslmed.aad1904
The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis.
Abstract
Jinkuk Choi1,2,*, Jie Gao1,2,*, Jaekwang Kim3,*, Cynthia Hong1,2, Jungsu Kim3,† and Peter Tontonoz1,2,†
1Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3Department of Neuroscience, Mayo Graduate School, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
†Corresponding author : Jungsu Kim, Peter Tontonoz
* These authors contributed equally to this work.
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.
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.
논문정보
- Research article
- 2015년 11월 (BRIC 등록일 2015-11-23)
- 국외 연구진
- 생명과학 > 신경생물학
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