Browsing by Author "Soni, Disha"

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    In vivo validation of late-onset Alzheimer's disease genetic risk factors
    (bioRxiv, 2023-12-24) Sasner, Michael; Preuss, Christoph; Pandey, Ravi S.; Uyar, Asli; Garceau, Dylan; Kotredes, Kevin P.; Williams, Harriet; Oblak, Adrian L.; Lin, Peter Bor-Chian; Perkins, Bridget; Soni, Disha; Ingraham, Cindy; Lee-Gosselin, Audrey; Lamb, Bruce T.; Howell, Gareth R.; Carter, Gregory W.; Radiology and Imaging Sciences, School of Medicine
    Introduction: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. Methods: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE4 and Trem2*R47H. Potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. Results: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. Discussion: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.
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    INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer’s disease
    (Wiley, 2023) Lin, Peter Bor-Chian; Tsai, Andy Po-Yi; Soni, Disha; Lee-Gosselin, Audrey; Moutinho, Miguel; Puntambekar, Shweta S.; Landreth, Gary E.; Lamb, Bruce T.; Oblak, Adrian L.; Anatomy, Cell Biology and Physiology, School of Medicine
    Introduction: Inositol polyphosphate-5-phosphatase (INPP5D) is a microglia-enriched lipid phosphatase in the central nervous system. A non-coding variant (rs35349669) in INPP5D increases the risk for Alzheimer's disease (AD), and elevated INPP5D expression is associated with increased plaque deposition. INPP5D negatively regulates signaling via several microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition on AD pathology remains unclear. Methods: We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis. Results: Inpp5d haplodeficiency perturbs the microglial intracellular signaling pathways regulating the immune response, including phagocytosis and clearing of amyloid beta (Aβ). It is important to note that Inpp5d haploinsufficiency leads to the preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by Inpp5d haploinsufficiency are related to synaptic regulation and immune cell activation. Conclusion: These data demonstrate that Inpp5d haplodeficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D is a potential therapeutic strategy for AD.
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    TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo
    (MDPI, 2023-06-10) Lee-Gosselin, Audrey; Jury-Garfe, Nur; You, Yanwen; Dabin, Luke; Soni, Disha; Dutta, Sayan; Rochet, Jean-Christophe; Kim, Jungsu; Oblak, Adrian L.; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
    The role of TREM2 in Alzheimer's disease (AD) is not fully understood. Previous studies investigating the effect of TREM2 deletion on tauopathy mouse models without the contribution of b-amyloid have focused only on tau overexpression models. Herein, we investigated the effects of TREM2 deficiency on tau spreading using a mouse model in which endogenous tau is seeded to produce AD-like tau features. We found that Trem2-/- mice exhibit attenuated tau pathology in multiple brain regions concomitant with a decreased microglial density. The neuroinflammatory profile in TREM2-deficient mice did not induce an activated inflammatory response to tau pathology. These findings suggest that reduced TREM2 signaling may alter the response of microglia to pathological tau aggregates, impairing their activation and decreasing their capacity to contribute to tau spreading. However, caution should be exercised when targeting TREM2 as a therapeutic entry point for AD until its involvement in tau aggregation and propagation is better understood.