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Browsing by Author "Lloyd, Christopher"
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Item Characterizing Molecular and Synaptic Signatures in mouse models of Late-Onset Alzheimer’s Disease Independent of Amyloid and Tau Pathology(bioRxiv, 2023-12-20) Kotredes, Kevin P.; Pandey, Ravi S.; Persohn, Scott; Elderidge, Kierra; Burton, Charles P.; Miner, Ethan W.; Haynes, Kathryn A.; Santos, Diogo Francisco S.; Williams, Sean-Paul; Heaton, Nicholas; Ingraham, Cynthia M.; Lloyd, Christopher; Garceau, Dylan; O’Rourke, Rita; Herrick, Sarah; Rangel-Barajas, Claudia; Maharjan, Surendra; Wang, Nian; Sasner, Michael; Lamb, Bruce T.; Territo, Paul R.; Sukoff Rizzo, Stacey J.; Carter, Gregory W.; Howell, Gareth R.; Oblak, Adrian L.; Medical and Molecular Genetics, School of MedicineIntroduction: MODEL-AD is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to more accurately mimic LOAD than commonly used transgenic models. Methods: We created the LOAD2 model by combining APOE4, Trem2*R47H, and humanized amyloid-beta. Mice aged up to 24 months were subjected to either a control diet or a high-fat/high-sugar diet (LOAD2+HFD) from two months of age. We assessed disease-relevant outcomes, including in vivo imaging, biomarkers, multi-omics, neuropathology, and behavior. Results: By 18 months, LOAD2+HFD mice exhibited cortical neuron loss, elevated insoluble brain Aβ42, increased plasma NfL, and altered gene/protein expression related to lipid metabolism and synaptic function. In vivo imaging showed age-dependent reductions in brain region volume and neurovascular uncoupling. LOAD2+HFD mice also displayed deficits in acquiring touchscreen-based cognitive tasks. Discussion: Collectively the comprehensive characterization of LOAD2+HFD mice reveal this model as important for preclinical studies that target features of LOAD independent of amyloid and tau.Item Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer's Disease-Relevant Phenotypes in Mice(Frontiers Media, 2022-06-24) Oblak, Adrian L.; Kotredes, Kevin P.; Pandey, Ravi S.; Reagan, Alaina M.; Ingraham, Cynthia; Perkins, Bridget; Lloyd, Christopher; Baker, Deborah; Lin, Peter B.; Soni, Disha M.; Tsai, Andy P.; Persohn, Scott A.; Bedwell, Amanda A.; Eldridge, Kierra; Speedy, Rachael; Meyer, Jill A.; Peters, Johnathan S.; Figueiredo, Lucas L.; Sasner, Michael; Territo, Paul R.; Sukoff Rizzo, Stacey J.; Carter, Gregory W.; Lamb, Bruce T.; Howell, Gareth R.; Radiology and Imaging Sciences, School of MedicineObesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model with APOE4 and a variant in triggering receptor expressed on myeloid cells 2 (Trem2R47H ). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (Plcg2M28L ) and the 677C > T variant in methylenetetrahydrofolate reductase (Mthfr 677C > T ) were engineered by CRISPR onto LOAD1 to generate LOAD1.Plcg2M28L and LOAD1.Mthfr 677C > T . At 2 months of age, animals were placed on an HFD that induces obesity or a control diet (CD), until 12 months of age. Throughout the study, blood was collected to assess the levels of cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. After the completion of the study, blood and brains were collected for analysis. As expected, animals fed a HFD, showed a significant increase in body weight compared to those fed a CD. Glucose increased as a function of HFD in females only with cholesterol increasing in both sexes. Interestingly, LOAD1.Plcg2M28L demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD. These changes were not observed in LOAD1 or LOAD1.Mthfr 677C > T animals fed with HFD. Furthermore, LOAD1.Plcg2M28L but not LOAD1.Mthfr 677C > T or LOAD1 animals showed transcriptomics correlations with human AD modules. Our results show that HFD affects the brain in a genotype-specific manner. Further insight into this process may have significant implications for the development of lifestyle interventions for the treatment of AD.