Browsing by Author "Smith, Daniel Curtis"

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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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    The Role of ABI3 in Obesity and Metabolic Regulation
    (2024-04) Smith, Daniel Curtis; Oblak, Adrian; Kim, Jungsu; Flak, Jonathan; Lasagna-Reeves, Cristian; Evans-Molina, Carmella
    Abelson Interactor Protein 3 is an adaptor protein involved in cytoskeletal remodeling. ABI3 is predominantly expressed within mononuclear phagocytotic immune cells within the brain, such as macrophages, peripherally, and microglia. Until recently, little was known about the function of the ABI3 protein, and even less was known regarding its role in disease. Following the identification of a rare mutation within ABI3 that increases the risk of developing Alzheimer’s disease, our laboratory began to investigate the impact of deleting Abi3 in mouse models. While we initially set out to investigate ABI3 in the context of neurodegeneration, we unexpectedly discovered that loss of Abi3 led to obesity in mice. This discovery and the subsequent efforts to uncover the mechanisms by which loss of Abi3 induces obesity are the subject of this dissertation. First, we demonstrate that deletion of Abi3 leads to severe obesity in aged mice. We identified significant Abi3-dependent transcriptomic changes within the hypothalamus, but not adipose tissue, of these mice. These changes occurred within pathways related to immune function, and subsequent immunostaining revealed decreased microglia number and area within the mediobasal hypothalamus of Abi3-/- mice. Next, we performed a longitudinal high-fat diet study to explore the impact of loss of Abi3 on mouse body weight and metabolic regulation during chronic nutrient excess and control conditions. Intriguingly, we found that only female Abi3-/- mice exhibited increased body weight during high-fat diet feeding. Subsequent transcriptomics from the hypothalamus of female Abi3+/+ and Abi3-/- mice from both high-fat and control diet groups revealed cytoskeletal-related changes only in the obese, high-fat diet-fed female Abi3-/- mice. Follow-up immunostaining revealed decreased microglia coverage within the mediobasal hypothalamus of the obese, high-fat diet-fed female Abi3-/- mice. While much remains to be explored regarding the precise role of ABI3 in the setting of energy balance regulation and obesity, our investigations revealed that loss of ABI3 is sufficient to induce obesity and appears to occur through altered microglia function within the hypothalamus. This dissertation represents a critical first step in the investigation of a novel regulator of obesity pathology.