Browsing by Author "Haynes, Kathryn A."

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    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 Medicine
    Introduction: 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.