Browsing by Author "Philtjens, Stéphanie"

Now showing 1 - 3 of 3
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    Deletion of miR‐33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice
    (Wiley, 2024) Tate, Mason; Wijeratne, H. R. Sagara; Kim, Byungwook; Philtjens, Stéphanie; You, Yanwen; Lee, Do-Hun; Gutierrez, Daniela A.; Sharify, Daniel; Wells, Megan; Perez-Cardelo, Magdalena; Doud, Emma H.; Fernandez-Hernando, Carlos; Lasagna-Reeves, Cristian; Mosley, Amber L.; Kim, Jungsu; Biochemistry and Molecular Biology, School of Medicine
    Introduction: Rare variants in ABCA1 increase the risk of developing Alzheimer's disease (AD). ABCA1 facilitates the lipidation of apolipoprotein E (apoE). This study investigated whether microRNA-33 (miR-33)-mediated regulation of this ABCA1-APOE pathway affects phenotypes of an amyloid mouse model. Methods: We generated mir-33+/+;APP/PS1 and mir-33-/-;APP/PS1 mice to determine changes in amyloid pathology using biochemical and histological analyses. We used RNA sequencing and mass spectrometry to identify the transcriptomic and proteomic changes between our genotypes. We also performed mechanistic experiments by determining the role of miR-33 in microglial migration and amyloid beta (Aβ) phagocytosis. Results: Mir-33 deletion increases ABCA1 levels and reduces Aβ accumulation and glial activation. Multi-omics studies suggested miR-33 regulates the activation and migration of microglia. We confirm that the inhibition of miR-33 significantly increases microglial migration and Aβ phagocytosis. Discussion: These results suggest that miR-33 might be a potential drug target by modulating ABCA1 level, apoE lipidation, Aβ level, and microglial function. Highlights: Loss of microRNA-33 (miR-33) increased ABCA1 protein levels and the lipidation of apolipoprotein E. Loss of miR-33 reduced amyloid beta (Aβ) levels, plaque deposition, and gliosis. mRNAs and proteins dysregulated by miR-33 loss relate to microglia and Alzheimer's disease. Inhibition of miR-33 increased microglial migration and Aβ phagocytosis in vitro.
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    Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis
    (Springer Nature, 2024-05-11) Kim, Byungwook; Dabin, Luke Child; Tate, Mason Douglas; Karahan, Hande; Sharify, Ahmad Daniel; Acri, Dominic J.; Al-Amin, Md Mamun; Philtjens, Stéphanie; Smith, Daniel Curtis; Wijeratne, H. R. Sagara; Park, Jung Hyun; Jucker, Mathias; Kim, Jungsu; Medical and Molecular Genetics, School of Medicine
    SPI1 was recently reported as a genetic risk factor for Alzheimer's disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-β (Aβ) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.
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    Network analysis identifies strain-dependent response to tau and tau seeding-associated genes
    (Rockefeller University Press, 2023) Acri, Dominic J.; You, Yanwen; Tate, Mason D.; Karahan, Hande; Martinez, Pablo; McCord, Brianne; Sharify, A. Daniel; John, Sutha; Kim, Byungwook; Dabin, Luke C.; Philtjens, Stéphanie; Wijeratne, H. R. Sagara; McCray, Tyler J.; Smith, Daniel C.; Bissel, Stephanie J.; Lamb, Bruce T.; Lasagna-Reeves, Cristian A.; Kim, Jungsu; Anatomy, Cell Biology and Physiology, School of Medicine
    Previous research demonstrated that genetic heterogeneity is a critical factor in modeling amyloid accumulation and other Alzheimer's disease phenotypes. However, it is unknown what mechanisms underlie these effects of genetic background on modeling tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT. To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n = 64) and determined core transcriptional signature conserved in all genetic backgrounds and signature unique to wild-derived backgrounds. By measuring tau seeding activity using the cortex, we identified 19 key genes associated with tau seeding and amyloid response. Interestingly, microglial pathways were strongly associated with tau seeding activity in CAST/EiJ and PWK/PhJ backgrounds. Collectively, our study demonstrates that mouse genetic context affects tau-mediated alteration of transcriptome and tau seeding. The gene modules associated with tau seeding provide an important resource to better model tauopathy.