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Neuronal Idol deletion ameliorates amyloid pathology

ABSTRACT: Earlier studies demonstrated that overexpression of the low-density lipoprotein receptor (LDLR) decreases apolipoprotein E (APOE) levels in the brain and alleviates amyloid-beta (Abeta) pathology. We hypothesized that inhibiting the Inducible Degrader of LDLR (IDOL)- an E3 ubiquitin ligase that ubiquitinates LDLR for degradation- would increase endogenous LDLR levels and decrease amyloid pathology. Previously, we demonstrated that the deletion of Idol increased LDLR levels and reduced amyloid deposition in a transgenic mouse model of Abeta-amyloidosis. However, the cellular mechanisms underlying these beneficial effects were unknown. Here, we investigate the cell-type-specific contribution of Idol deletion to amyloid pathology by generating Idol conditional knock-out mouse models. We demonstrate that deletion of neuronal, but not microglial, Idol reduces amyloid accumulation in the 5XFAD transgenic mouse model. Furthermore, only neuronal Idol deletion alters brain LDLR and APOE levels, pointing to the critical role of the neuronal LDLR-APOE axis in modulating Abeta accumulation.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jungsu Kim

PROVIDER: MSV000098209 | MassIVE | Mon Jun 16 02:16:00 BST 2025

SECONDARY ACCESSION(S): PXD065038

REPOSITORIES: MassIVE

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Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.

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Neuronal Idol deletion ameliorates amyloid pathology

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