Browsing by Author "Lee-Gosselin, Audrey"

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    Bassoon contributes to tau-seed propagation and neurotoxicity
    (Springer Nature, 2022) Martinez, Pablo; Patel, Henika; You, Yanwen; Jury, Nur; Perkins, Abigail; Lee-Gosselin, Audrey; Taylor, Xavier; You, Yingjian; Di Prisco, Gonzalo Viana; Huang, Xiaoqing; Dutta, Sayan; Wijeratne, Aruna B.; Redding-Ochoa, Javier; Shahid, Syed Salman; Codocedo, Juan F.; Min, Sehong; Landreth, Gary E.; Mosley, Amber L.; Wu, Yu-Chien; McKinzie, David L.; Rochet, Jean-Christophe; Zhang, Jie; Atwood, Brady K.; Troncoso, Juan; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
    Tau aggregation is a defining histopathological feature of Alzheimer’s disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer’s disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.
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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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    Inpp5d haplodeficiency alleviates tau pathology in the PS19 mouse model of Tauopathy
    (Wiley, 2024) Soni, Disha M.; Bor-Chian Lin, Peter; Lee-Gosselin, Audrey; Lloyd, Christopher D.; Mason, Emily; Ingraham, Cynthia M.; Perkins, Abigail; Moutinho, Miguel; Lamb, Bruce T.; Chu, Shaoyou; Oblak, Adrian L.; Neurology, School of Medicine
    Introduction: A noncoding variant (rs35349669) within INPP5D, a lipid and protein phosphatase restricted to microglia in the brain, is linked to increased susceptibility to Alzheimer's disease (AD). While Inpp5d is well-studied in amyloid pathology, its role in tau pathology remains unclear. Methods: PS19 Tauopathy mice were crossed with Inpp5d-haplodeficient (Inpp5d+/-) mice to examine the impact of Inpp5d in tau pathology. Results: Increased INPP5D expression correlated positively with phospho-Tau AT8 in PS19 mice. Inpp5d haplodeficiency mitigated hyperphosphorylated tau levels (AT8, AT180, AT100, and PHF1) and motor deficits in PS19 mice. Transcriptomic analysis revealed an up-regulation of genes associated with immune response and cell migration. Discussion: Our findings define an association between INPP5D expression and tau pathology in PS19 mice. Alleviation in hyperphosphorylated tau, motor deficits, and transcriptomics changes in haplodeficient-Inpp5d PS19 mice indicate that modulation in INPP5D expression may provide therapeutic potential for mitigating tau pathology and improving motor deficits. Highlights: The impact of Inpp5d in the context of tau pathology was studied in the PS19 mouse model. INPP5D expression is associated with tau pathology. Reduced Inpp5d expression in PS19 mice improved motor functions and decreased total and phospho-Tau levels. Inpp5d haplodeficiency in PS19 mice modulates gene expression patterns linked to immune response and cell migration. These data suggest that inhibition of Inpp5d may be a therapeutic approach in tauopathies.
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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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    Optimization of SHIP1 Inhibitors for the treatment of Alzheimer’s disease
    (Wiley, 2025-01-09) Jesudason, Cynthia D.; Lin, Peter Bor-Chian; Soni, Disha; Perkins, Bridget M.; Lee-Gosselin, Audrey; Ingraham, Cynthia M.; Hamilton, Will; Mason, Emily R.; El Jordi, Omar; Souza, Sarah; Jacobson, Marlene; Di Salvo, Jerry; Clayton, Brent; Chu, Shaoyou; Dage, Jeffrey L.; Oblak, Adrian L.; Richardson, Timothy I.; Neurology, School of Medicine
    Background: SHIP1 is a phosphatidyl inositol phosphatase encoded by INPP5D, which has been identified as a risk gene for Alzheimer’s disease (AD). SHIP1 is expressed in microglia, the resident macrophage in brain. It is a complex, multidomain protein that acts as a negative regulator downstream from TREM2. SHIP1 possesses a phosphatase (Ptase) domain flanked by a pleckstrin‐homology (PH) domain that binds phosphatidylinositol (3,4,5)‐trisphosphate[PI(3,4,5)P3] and a C2 domain that binds phosphatidylinositol (3,4)‐bisphosphate [PI(3,4)P2]. The Ptase domain converts PI(3,4,5)P3 to PI(3,4)P2. SHIP1 also has an SH2 domain that binds to ITIMs and ITAMs where it competes with kinases. Inhibiting SHIP1 is hypothesized to have potential therapeutic benefits, as it may improve TREM2‐mediated microglial responses to neurotoxins and promote an overall neuroprotective microglial phenotype to maintain a more resilient brain and slow the rate of cognitive decline in AD patients. Method: The IUSM Purdue TREAT‐AD Center recently evaluated SHIP1 inhibitors and proposed 3‐((2,4‐Dichlorobenzyl)oxy)‐5‐(1‐(piperidin‐4‐yl)‐1H‐pyrazol‐4‐yl)pyridine for target validation studies. Structurally related analogs were synthesized and tested for SHIP1 enzyme inhibition, AKT signaling, and microglia activation in a high‐content imaging assay using HMC3 and BV2 microglia‐like cell lines. Primary microglia were treated with an optimized SHIP1 inhibitor, and subsequent changes in fibril Aβ uptake and cell viability were assessed. The NanoString nCounter Neuroinflammation assay was used to measure transcriptomic profiles. For comparison primary microglial derived from both wild‐type and Inpp5d‐haploinsufficient mice were assessed. Result: Novel SHIP1 inhibitors have been discovered and preliminary Structure Activity Relationship (SAR) studies have been completed. These compounds have shown positive results for biochemical activity, target engagement and cellular pharmacology. Both Inpp5d deficiency and pharmacological inhibition increase amyloid uptake and cell viability in primary microglia. Elevated ERK and AKT phosphorylation, after amyloid exposure, were decreased by Inpp5d deficiency. Functional pathways associated with phagocytosis, apoptosis, cytokine production, and complement system activity were altered. Conclusion: These data demonstrate that SHIP1 inhibition promotes amyloid uptake through the complement system. SHIP1 inhibition also enhances cell survival and homeostasis in primary microglia. Further studies of SHIP1 inhibition and INPP5D knockdown in animal models may provide a potential therapeutic strategy for Alzheimer’s disease.
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    TONSL is an immortalizing oncogene and a therapeutic target in breast cancer
    (American Association for Cancer Research, 2023) Khatpe, Aditi S.; Dirks, Rebecca; Bhat-Nakshatri, Poornima; Mang, Henry; Batic, Katie; Swiezy, Sarah; Olson, Jacob; Rao, Xi; Wang, Yue; Tanaka, Hiromi; Liu, Sheng; Wan, Jun; Chen, Duojiao; Liu, Yunlong; Fang, Fang; Althouse, Sandra; Hulsey, Emily; Granatir, Maggie M.; Addison, Rebekah; Temm, Constance J.; Sandusky, George; Lee-Gosselin, Audrey; Nephew, Kenneth; Miller, Kathy D.; Nakshatri, Harikrishna; Surgery, School of Medicine
    Study of genomic aberrations leading to immortalization of epithelial cells has been technically challenging due to the lack of isogenic models. To address this, we utilized healthy primary breast luminal epithelial cells of different genetic ancestry and their hTERT-immortalized counterparts to identify transcriptomic changes associated with immortalization. Elevated expression of TONSL (Tonsoku Like, DNA Repair Protein) was identified as one of the earliest events during immortalization. TONSL, which is located on chromosome 8q24.3, was found to be amplified in ~20% of breast cancers. TONSL alone immortalized primary breast epithelial cells and increased telomerase activity, but overexpression was insufficient for neoplastic transformation. However, TONSL-immortalized primary cells overexpressing defined oncogenes generated estrogen receptor-positive adenocarcinomas in mice. Analysis of a breast tumor microarray with ~600 tumors revealed poor overall and progression free survival of patients with TONSL overexpressing tumors. TONSL increased chromatin accessibility to pro-oncogenic transcription factors including NF-κB and limited access to the tumor suppressor p53. TONSL overexpression resulted in significant changes in the expression of genes associated with DNA repair hubs, including upregulation of several genes in the homologous recombination (HR) and Fanconi Anemia pathways. Consistent with these results, TONSL overexpressing primary cells exhibited upregulated DNA repair via HR. Moreover, TONSL was essential for growth of TONSL-amplified breast cancer cell lines in vivo, and these cells were sensitive to TONSL-FACT complex inhibitor CBL0137. Together, these findings identify TONSL as a regulator of epithelial cell immortalization to facilitate cancer initiation and as a target for breast cancer therapy.
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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.