Document Type
Article
Publication Date
6-1-2024
Original Citation
Kotredes K,
Pandey R,
Persohn S,
Elderidge K,
Burton C,
Miner E,
Haynes K,
Santos D,
Williams S,
Heaton N,
Ingraham C,
Lloyd C,
Garceau D,
O'Rourke R,
Herrick S,
Rangel-Barajas C,
Maharjan S,
Wang N,
Sasner M,
Lamb B,
Territo P,
Sukoff Rizzo S,
Carter GW,
Howell G,
Oblak A.
Characterizing molecular and synaptic signatures in mouse models of late-onset Alzheimer's disease independent of amyloid and tau pathology. Alzheimers Dement. 2024;20(6):4126-46.
Keywords
JGM, JMG, Animals, Alzheimer Disease, Disease Models, Animal, Mice, Amyloid beta-Peptides, tau Proteins, Mice, Transgenic, Brain, Synapses, Male, Female, Humans
JAX Source
Alzheimers Dement. 2024;20(6):4126-46.
ISSN
1552-5279
PMID
38735056
DOI
https://doi.org/10.1002/alz.13828
Grant
Data collec- tion was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG36836 (RNAseq), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Insti- tute (genomic). Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. The Brain and Body Donation Program was supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Ari- zona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson’s Research. The MODEL-AD Center was supported through fund- ing by NIA grant U54AG054345. GH was supported by the Diana Davis Spencer Endowed Chair Research and GC was supported by the Bernard and Lusia Milch Endowed Chair. NW was supported by NINDS grant R01NS125020.
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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