Browsing by Author "Sharify, Daniel"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    Loss of Inpp5d has disease‐relevant and sex‐specific effects on glial transcriptomes
    (Wiley, 2024) Dabin, Luke C.; Kersey, Holly; Kim, Byungwook; Acri, Dominic J.; Sharify, Daniel; Lee-Gosselin, Audrey; Lasagna-Reeves, Cristian A.; Oblak, Adrian L.; Lamb, Bruce T.; Kim, Jungsu; Medical and Molecular Genetics, School of Medicine
    Introduction: Inpp5d is genetically associated with Alzheimer's disease risk. Loss of Inpp5d alters amyloid pathology in models of amyloidosis. Inpp5d is expressed predominantly in microglia but its function in brain is poorly understood. Methods: We performed single-cell RNA sequencing to study the effect of Inpp5d loss on wild-type mouse brain transcriptomes. Results: Loss of Inpp5d has sex-specific effects on the brain transcriptome. Affected genes are enriched for multiple neurodegeneration terms. Network analyses reveal a gene co-expression module centered around Inpp5d in female mice. Inpp5d loss alters Pleotrophin (PTN), Prosaposin (PSAP), and Vascular Endothelial Growth Factor A (VEGFA) signaling probability between cell types. Discussion: Our data suggest that the normal function of Inpp5d is entangled with mechanisms involved in neurodegeneration. We report the effect of Inpp5d loss without pathology and show that this has dramatic effects on gene expression. Our study provides a critical reference for researchers of neurodegeneration, allowing separation of disease-specific changes mediated by Inpp5d in disease from baseline effects of Inpp5d loss. Highlights: Loss of Inpp5d has different effects in male and female mice. Genes dysregulated by Inpp5d loss relate to neurodegeneration. Total loss of Inpp5d in female mice collapses a conserved gene co-expression module. Loss of microglial Inpp5d affects the transcriptome of other cell types.