Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice
Year: 2020
Type: article
Abstract: Brain lipoprotein receptors have been shown to regulate the metabolism of ApoE and β-amyloid (Aβ) and are potential therapeutic targets for Alzheimer’s disease (AD). Previously, we identified E3 ubiquitin ligase IDOL as a negative regulator of brain lipoprotein receptors. Genetic ablation of Idol increases low-density lipoprotein receptor protein levels, which facilitates Aβ uptake and clearance by microglia. In this study, we utilized an antisense oligonucleotide (ASO) to reduce IDOL expression therapeutically in the brains of APP/PS1 male mice. ASO treatment led to decreased Aβ pathology and improved spatial learning and memory. Single-cell transcriptomic analysis of hippocampus revealed that IDOL inhibition upregulated lysosomal/phagocytic genes in microglia. Furthermore, clustering of microglia revealed that IDOL-ASO treatment shifted the composition of the microglia population by increasing the prevalence of disease-associated microglia. Our results suggest that reducing IDOL expression in the adult brain promotes the phagocytic clearance of Aβ and ameliorates Aβ-dependent pathology. Pharmacological inhibition of IDOL activity in the brain may represent a therapeutic strategy for the treatment of AD.
Source: Molecular and Cellular Biology
DOI: 10.1128/mcb.00518-19
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, U.S. National Library of Medicine
Awards: The Idol-ApoE receptor pathway in Alzheimer's disease, Cell-specific novel genomic biomarkers of TBI pathology, Lipid-Responsive E3 ubiquitin ligases in cholesterol metabolism and atheroscierosis, Biomedical Big Data Training Grant, Biomedical Big Data Training Grant, G687939443, DHA Reverses Gene Network Signatures of Fructose-induced Metabolic Syndrome, Training in Molecular Toxicology
OpenAlex ID: W3002043434