Browsing by Author "Bissel, Stephanie"

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    APOE4 Drives Impairment in Astrocyte-Neuron Coupling in Alzheimer's Disease and Works Through Mechanisms in Early Disease to Influence Pathology
    (2023-05) Brink, Danika Marie Tumbleson; Lamb, Bruce; Bissel, Stephanie; Herbert, Brittney-Shea; Landreth, Gary; Puntambekar, Shweta; Saykin, Andrew; Zhang, Chi
    Alzheimer’s disease (AD) is a neurodegenerative disorder resulting in progressive memory loss, brain atrophy, and eventual death. AD pathology is characterized by the accumulation of neurotoxic amyloid-beta (Aβ) plaques, synapse loss, neurofibrillary tangles (NFTs), and neurodegeneration. The APOE4 allele is associated with a 3-fold increased risk for AD and results in increased Aβ plaque deposition, reduced Aβ clearance, and reduced synaptic plasticity. Although APOE expression is upregulated in microglia in AD, APOE is expressed primarily by astrocytes in the CNS. It is not well understood how astrocytic APOE drives the mechanisms that result in worsened AD outcomes. Here, digital spatial profiling and bioinformatics data suggest that APOE4 causes transcriptional dysregulation in early AD and may disrupt neuronal processes via astrocytes. Whole transcriptome data from plaque and non-plaque regions in the cortices and hippocampus of 4- and 8-month-old AD model mice expressing humanized APOE4/4 or APOE3/3 (control) were analyzed. Transcriptional dysregulation was increased in APOE4/4 AD mice compared to that in APOE3/3 at 4 but not 8 months of age, suggesting that early dysregulation of APOE4-driven disease mechanisms may shape degenerative outcomes in late-stage AD. Additionally, APOE4/4 potentially functions via plaque-independent mechanisms to influence neuronal function in early AD before the onset of pathology. Single-nuclei RNA sequencing data were obtained from human post-mortem astrocytes and the bioinformatic analyses revealed a novel astrocyte subtype that highly expresses several top genes involved in functional alterations associated with APOE4, including neuronal generation, development, and differentiation, and synaptic transmission and organization. Overall, our findings indicate that APOE4 may drive degenerative outcomes through the presented astrocyte candidate pathways. These pathways represent potential targets for investigations into early intervention strategies for APOE4/4 patients.
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    IL-34 exacerbates pathogenic features of Alzheimer’s disease and calvaria osteolysis in triple transgenic (3x-Tg) female mice
    (Elsevier, 2023) Ho, Anny; Ngala, Bidii; Yamada, Chiaki; Garcia, Christopher; Duarte, Carolina; Akkaoui, Juliet; Ciolac, Dumitru; Nusbaum, Amilia; Kochen, William; Efremova, Daniela; Groppa, Stanislav; Nathanson, Lubov; Bissel, Stephanie; Oblak, Adrian; Kacena, Melissa A.; Movila, Alexandru; Biomedical and Applied Sciences, School of Dentistry
    Hallmark features of Alzheimer’s disease (AD) include elevated accumulation of aggregated Aβ40 and Aβ42 peptides, hyperphosphorylated Tau (p-Tau), and neuroinflammation. Emerging evidence indicated that interleukin-34 (IL-34) contributes to AD and inflammatory osteolysis via the colony-stimulating factor-1 receptor (CSF-1r). In addition, CSF-1r is also activated by macrophage colony-stimulating factor-1 (M-CSF). While the role of M-CSF in bone physiology and pathology is well addressed, it remains controversial whether IL-34-mediated signaling promotes osteolysis, neurodegeneration, and neuroinflammation in relation to AD. In this study, we injected 3x-Tg mice with mouse recombinant IL-34 protein over the calvaria bone every other day for 42 days. Then, behavioral changes, brain pathology, and calvaria osteolysis were evaluated using various behavioral maze and histological assays. We demonstrated that IL-34 administration dramatically elevated AD-like anxiety and memory loss, pathogenic amyloidogenesis, p-Tau, and RAGE expression in female 3x-Tg mice. Furthermore, IL-34 delivery promoted calvaria inflammatory osteolysis compared to the control group. In addition, we also compared the effects of IL-34 and M-CSF on macrophages, microglia, and RANKL-mediated osteoclastogenesis in relation to AD pathology in vitro. We observed that IL-34-exposed SIM-A9 microglia and 3x-Tg bone marrow-derived macrophages released significantly elevated amounts of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6, compared to M-CSF treatment in vitro. Furthermore, IL-34, but not M-CSF, elevated RANKL-primed osteoclastogenesis in the presence of Aβ40 and Aβ42 peptides in bone marrow derived macrophages isolated from female 3x-Tg mice. Collectively, our data indicated that IL-34 elevates AD-like features, including behavioral changes and neuroinflammation, as well as osteoclastogenesis in female 3x-Tg mice.
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    Utilization of a Human Induced Pluripotent Stem Cell Model of Microglial Fractalkine Signaling Dysfunction in Alzheimer's Disease
    (2025-03) Tutrow, Kaylee D.; Meyer, Jason; Bissel, Stephanie; Kim, Jungsu; Lasagna-Reeves, Cristian
    Dysfunctional microglial activity has been identified as a potential mechanism leading to accumulation of amyloid beta and pTau and subsequent neurodegeneration in Alzheimer's Disease (AD). The CX3CR1/fractalkine axis serves as a mechanism for bidirectional communication between microglia and neurons, respectively, to promote an anti-inflammatory microglial state. Previous studies have demonstrated that deficiency in CX3CR1 signaling leads microglia to develop a more pro-inflammatory phenotype, induces phagocytic deficits, and increases susceptibility of neurons to cell death. The CX3CR1-V249I polymorphism was recently identified as a potential risk allele for AD. However, the role offractalk:ine dysfunction in human cells and the mechanisms by which microglia with the CX3CR1-V249I SNP contribute to neurodegeneration remain unclear. To address this shortcoming, we utilized human induced pluripotent stem cells and CRISPR/Cas9 technology to elucidate the effects of the V249I polymorphism on human microglia-like cells (hMGLs). We demonstrate effective differentiation from paired isogenic control and CX3CR1-V249I backgrounds into hMGLs. Transcriptional profiling via RNA-seq analyses demonstrated alterations in pathways such as apoptosis, toll-like receptor signaling, and the inflammasome due to the CX3CR1-V249I SNP. Both heterozygous and homozygous microglia bearing the V249I allele demonstrated decreased phagocytosis of amyloid beta in vitro compared to controls, with this effect modulated by the presence of fractalkine in heterozygous but not homozygous V249I hMGLs. Both heterozygous and homozygous V249I microglia exhibited increased stress-induced cell death compared to controls, with homozygous hMGLs demonstrating increased cell death at earlier time points. These findings suggest that the CX3CR1-V249I polymorphism may confer a dysfunctional microglia phenotype, which may subsequently contribute to neuronal dysfunction. Further investigation of microglia in neuron co-culture models demonstrated that the CX3CR1-V249I variant conferred altered neuronal excitability. Collectively, the results of this study highlight the importance of understanding CX3CR1 function in AD pathology to identify targetable mechanisms for intervention.