Research ArticleAlzheimer’s Disease

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

Science Translational Medicine  18 Nov 2015:
Vol. 7, Issue 314, pp. 314ra184
DOI: 10.1126/scitranslmed.aad1904

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Idolizing a treatment for Alzheimer’s disease

A hallmark feature of Alzheimer’s disease is the accumulation of a protein called β-amyloid (Aβ) in the brain. In their study, Choi et al. demonstrate that Idol, a protein linked to cholesterol metabolism, also has a crucial role in the development of Alzheimer’s-like disease in mice. Mice engineered to lack Idol were protected from developing Aβ deposits. The authors further showed that this protection was associated with better clearance of Aβ and apolipoprotein E by macrophage-like brain cells called microglia. This discovery suggests that the Idol pathway may be a therapeutic target for preventing the formation of Alzheimer’s disease lesions.

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.

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