| First Author | Gao J | Year | 2020 |
| Journal | Mol Cell Biol | Volume | 40 |
| Issue | 8 | PubMed ID | 31964754 |
| Mgi Jnum | J:292288 | Mgi Id | MGI:6447755 |
| Doi | 10.1128/MCB.00518-19 | Citation | Gao J, et al. (2020) Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice. Mol Cell Biol 40(8) |
| abstractText | Brain lipoprotein receptors have been shown to regulate the metabolism of ApoE and beta-amyloid (Abeta) 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 Abeta 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 Abeta 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 Abeta and ameliorates Abeta-dependent pathology. Pharmacological inhibition of IDOL activity in the brain may represent a therapeutic strategy for the treatment of AD. |
