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.

中文翻译：

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治疗性 IDOL 减少可改善 APP/PS1 小鼠的淀粉样变性并改善认知功能。


脑脂蛋白受体已被证明可以调节 ApoE 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。此前，我们确定 E3 泛素连接酶 IDOL 是脑脂蛋白受体的负调节因子。 Idol 的基因消融增加了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) 来治疗性地减少 APP/PS1 雄性小鼠大脑中 IDOL 的表达。 ASO 治疗可减少 Aβ 病理并改善空间学习和记忆。海马体的单细胞转录组分析表明，IDOL 抑制上调了小胶质细胞中的溶酶体/吞噬细胞基因。此外，小胶质细胞的聚集表明，IDOL-ASO 治疗通过增加与疾病相关的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，减少成人大脑中 IDOL 的表达可促进 Aβ 的吞噬细胞清除并改善 Aβ 依赖性病理。对大脑中 IDOL 活性的药理学抑制可能是治疗 AD 的一种治疗策略。