Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
Department of Integrative Biology and Physiology, University of California-Los Angeles, Los Angeles, California, USA.
Mol Cell Biol. 2020 Mar 30;40(8). doi: 10.1128/MCB.00518-19.
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 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.
脑脂蛋白受体已被证明可调节载脂蛋白 E 和 β-淀粉样蛋白 (Aβ) 的代谢，是阿尔茨海默病 (AD) 的潜在治疗靶点。先前，我们发现 E3 泛素连接酶 IDOL 是脑脂蛋白受体的负调节剂。降低 IDOL 的表达会增加低密度脂蛋白受体蛋白水平，从而促进小胶质细胞摄取和清除 Aβ。在这项研究中，我们利用反义寡核苷酸 (ASO) 在 APP/PS1 雄性小鼠的大脑中进行 IDOL 的治疗性敲低。ASO 治疗可降低 Aβ 病理，并改善空间学习和记忆。对海马体的单细胞转录组分析显示，IDOL 抑制可上调小胶质细胞中的溶酶体/吞噬基因。此外，小胶质细胞聚类分析显示，IDOL-ASO 治疗通过增加疾病相关小胶质细胞的患病率来改变小胶质细胞群体的组成。我们的结果表明，降低成年大脑中的 IDOL 表达可促进 Aβ 的吞噬清除，并改善 Aβ 依赖性病理。在大脑中抑制 IDOL 活性可能是治疗 AD 的一种治疗策略。
