Browsing by Author "Dabin, Luke C."

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    Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aβ amyloidosis
    (American Association for the Advancement of Science, 2021-11) Karahan, Hande; Smith, Daniel C.; Kim, Byungwook; Dabin, Luke C.; Al-Amin, Md Mamun; Wijeratne, H.R. Sagara; Pennington, Taylor; di Prisco, Gonzalo Viana; McCord, Brianne; Lin, Peter Bor-Chian; Li, Yuxin; Peng, Junmin; Oblak, Adrian L.; Chu, Shaoyou; Atwood, Brady K.; Kim, Jungsu; Medical and Molecular Genetics, School of Medicine
    Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of Alzheimer’s disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid β (Aβ) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD;Abi3 knockout (“Abi3−/−”) mice. Moreover, we identified marked changes in the proportion of microglia subpopulations in Abi3−/− mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Aβ accumulation and neuroinflammation.
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    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.
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    MicroRNAs on the move: microRNAs in astrocyte-derived ApoE particles regulate neuronal function
    (Elsevier, 2021) Karahan, Hande; Dabin, Luke C.; Tate, Mason D.; Kim, Jungsu; Medical and Molecular Genetics, School of Medicine
    In this issue of Neuron, Li et al. (2021) demonstrate that ApoE lipoprotein particles shuttle miRNAs from astrocytes to neurons, leading to inhibition of cholesterol biosynthesis and an increase in histone acetylation in neurons.
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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.
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    Robust single nucleus RNA sequencing reveals depot-specific cell population dynamics in adipose tissue remodeling during obesity
    (bioRxiv, 2024-04-08) So, Jisun; Strobel, Olivia; Wann, Jamie; Kim, Kyungchan; Paul, Avishek; Acri, Dominic J.; Dabin, Luke C.; Kim, Jungsu; Roh, Hyun Cheol; Biochemistry and Molecular Biology, School of Medicine
    Single nucleus RNA sequencing (snRNA-seq), an alternative to single cell RNA sequencing (scRNA-seq), encounters technical challenges in obtaining high-quality nuclei and RNA, persistently hindering its applications. Here, we present a robust technique for isolating nuclei across various tissue types, remarkably enhancing snRNA-seq data quality. Employing this approach, we comprehensively characterize the depot-dependent cellular dynamics of various cell types underlying adipose tissue remodeling during obesity. By integrating bulk nuclear RNA-seq from adipocyte nuclei of different sizes, we identify distinct adipocyte subpopulations categorized by size and functionality. These subpopulations follow two divergent trajectories, adaptive and pathological, with their prevalence varying by depot. Specifically, we identify a key molecular feature of dysfunctional hypertrophic adipocytes, a global shutdown in gene expression, along with elevated stress and inflammatory responses. Furthermore, our differential gene expression analysis reveals distinct contributions of adipocyte subpopulations to the overall pathophysiology of adipose tissue. Our study establishes a robust snRNA-seq method, providing novel insights into the mechanisms orchestrating adipose tissue remodeling during obesity, with broader applicability across diverse biological systems.
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    The effect of Abi3 locus deletion on the progression of Alzheimer's disease-related pathologies
    (Frontiers Media, 2023-02-21) Karahan, Hande; Smith, Daniel C.; Kim, Byungwook; McCord, Brianne; Mantor, Jordan; John, Sutha K.; Al-Amin, Md Mamun; Dabin, Luke C.; Kim, Jungsu; Medical and Molecular Genetics, School of Medicine
    Human genetics studies of Alzheimer’s disease (AD) have identified the ABI3 gene as a candidate risk gene for AD. Because ABI3 is highly expressed in microglia, the brain’s immune cells, it was suggested that ABI3 might impact AD pathogenesis by regulating the immune response. Recent studies suggest that microglia have multifaceted roles in AD. Their immune response and phagocytosis functions can have beneficial effects in the early stages of AD by clearing up amyloid-beta (Aβ) plaques. However, they can be harmful at later stages due to their continuous inflammatory response. Therefore, it is important to understand the role of genes in microglia functions and their impact on AD pathologies along the progression of the disease. To determine the role of ABI3 at the early stage of amyloid pathology, we crossed Abi3 knock-out mice with the 5XFAD Aβ-amyloidosis mouse model and aged them until 4.5-month-old. Here, we demonstrate that deletion of the Abi3 locus increased Aβ plaque deposition, while there was no significant change in microgliosis and astrogliosis. Transcriptomic analysis indicates alterations in the expression of immune genes, such as Tyrobp, Fcer1g, and C1qa. In addition to the transcriptomic changes, we found elevated cytokine protein levels in Abi3 knock-out mouse brains, strengthening the role of ABI3 in neuroinflammation. These findings suggest that loss of ABI3 function may exacerbate AD progression by increasing Aβ accumulation and inflammation starting from earlier stages of the pathology.