title: The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis.
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.
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jinkuk
authors.initials: J
authors.lastname: Choi
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Neuroscience, Mayo Graduate School, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Kim
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.affiliation: Department of Neuroscience, Mayo Graduate School, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. ptontonoz@mednet.ucla.edu kim.jungsu@mayo.edu.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. ptontonoz@mednet.ucla.edu kim.jungsu@mayo.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D058225:Plaque, Amyloid; D059748:Proteolysis; D011973:Receptors, LDL / Q000378:metabolism*; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D011973:Receptors, LDL; C542022:Mylip protein, mouse; D044767:Ubiquitin-Protein Ligases