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首页> 外文期刊>Molecular and Cellular Biology >Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice
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Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice

机译：Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice

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摘要

Brain lipoprotein receptors have been shown to regulate the metabolism of ApoE and 13-amyloid (A beta) 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 lowdensity lipoprotein receptor protein levels, which facilitates A beta uptake and clearance by microglia. In this study, we utilized an antisense oligonucleotide (ASO) to reduce IDOL expression therapeutically in the brains of APP/PSI male mice. ASO treatment led to decreased A beta 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 A beta and ameliorates A beta-dependent pathology. Pharmacological inhibition of IDOL activity in the brain may represent a therapeutic strategy for the treatment of AD.

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