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Transcriptomic analysis of microglia from young and aged wild-type, NLRP3-/-, APP/PS1 and APP/PS1.NLRP3-/- mice.

ABSTRACT: Activation of the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer’s disease (AD), via the characterised release of IL-1β and ASC specks. However, whether NLRP3 was involved in pathways beyond this remained unknown. Here were enriched CD11b+ cells from the brains of 4, 6 an 12 month old wild-type, NLRP3-/-, APP/PS1 and APP/PS1.NLRP3-/- mice for bulk RNA sequencing. We found that amyloid deposition was associated with an increase in the expression of genes encoding inflammatory or phagocytic proteins from 6 months onwards. Interestingly, loss of NLRP3 influences glutamine/glutamate-related metabolism and increases expression of microglial Slc1a3. The increase in Slc1a3 was observed in all mice on a NLRP3-/- background and at all ages examined, demonstrating a new role for this transporter in microglia.

ORGANISM(S): Mus musculus

PROVIDER: GSE269886 | GEO | 2025/02/03

REPOSITORIES: GEO

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	GSE269886_raw_count_matrix.txt.gz	Txt

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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.

Dataset Information

Transcriptomic analysis of microglia from young and aged wild-type, NLRP3-/-, APP/PS1 and APP/PS1.NLRP3-/- mice.

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