Abstract
INTRODUCTION
MODEL-AD (Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease) is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory and progression of late-onset Alzheimer’s disease (LOAD) more accurately.
METHODS
We created the LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, and humanized amyloid-beta (Aβ). Mice were subjected to a control diet or a high-fat/high-sugar diet (LOAD2+HFD). We assessed disease-relevant outcome measures in plasma and brain including neuroinflammation, Aβ, neurodegeneration, neuroimaging, and multi-omics.
RESULTS
By 18 months, LOAD2+HFD mice exhibited sex-specific neuron loss, elevated insoluble brain Aβ42, increased plasma neurofilament light chain (NfL), and altered gene/protein expression related to lipid metabolism and synaptic function. Imaging showed reductions in brain volume and neurovascular uncoupling. Deficits in acquiring touchscreen-based cognitive tasks were observed.
DISCUSSION
The comprehensive characterization of LOAD2+HFD mice reveals that this model is important for preclinical studies seeking to understand disease trajectory and progression of LOAD prior to or independent of amyloid plaques and tau tangles.
Highlights
By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2+HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble Ab42 in the brain, and increased plasma neurofilament light chain (NfL).
Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease-relevant processes including lipid metabolism and synaptic function.
In vivo imaging revealed an age-dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT).
LOAD2+HFD mice also demonstrated deficits in acquisition of touchscreen-based cognitive tasks.
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This post is Copyright: Kevin P. Kotredes,
Ravi S. Pandey,
Scott Persohn,
Kierra Elderidge,
Charles P Burton,
Ethan W. Miner,
Kathryn A. Haynes,
Diogo Francisco S. Santos,
Sean‐Paul Williams,
Nicholas Heaton,
Cynthia M. Ingraham,
Christopher Lloyd,
Dylan Garceau,
Rita O’Rourke,
Sarah Herrick,
Claudia Rangel‐Barajas,
Surendra Maharjan,
Nian Wang,
Michael Sasner,
Bruce T. Lamb,
Paul R. Territo,
Stacey J. Sukoff Rizzo,
Gregory W. Carter,
Gareth R. Howell,
Adrian L. Oblak | May 13, 2024