Characterizing molecular and synaptic signatures in mouse models of late-onset Alzheimer's disease independent of amyloid and tau pathology.

Autor: Kotredes KP; The Jackson Laboratory, Bar Harbor, Maine, USA., Pandey RS; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA., Persohn S; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA., Elderidge K; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA., Burton CP; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA., Miner EW; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA., Haynes KA; Department of Medicine, University of Pittsburgh Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Santos DFS; Department of Medicine, University of Pittsburgh Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Williams SP; Department of Medicine, University of Pittsburgh Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Heaton N; Department of Medicine, University of Pittsburgh Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Ingraham CM; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA., Lloyd C; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA., Garceau D; The Jackson Laboratory, Bar Harbor, Maine, USA., O'Rourke R; The Jackson Laboratory, Bar Harbor, Maine, USA., Herrick S; The Jackson Laboratory, Bar Harbor, Maine, USA., Rangel-Barajas C; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA., Maharjan S; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA.; Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA., Wang N; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA.; Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA., Sasner M; The Jackson Laboratory, Bar Harbor, Maine, USA., Lamb BT; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA., Territo PR; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA.; Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA., Sukoff Rizzo SJ; Department of Medicine, University of Pittsburgh Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Carter GW; The Jackson Laboratory, Bar Harbor, Maine, USA.; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.; Tufts University Graduate School of Biomedical Sciences, Boston, Massachusetts, USA.; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA., Howell GR; The Jackson Laboratory, Bar Harbor, Maine, USA.; Tufts University Graduate School of Biomedical Sciences, Boston, Massachusetts, USA.; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA., Oblak AL; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indianapolis, Indiana, USA.; Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Jazyk: angličtina
Zdroj: Alzheimer's & dementia : the journal of the Alzheimer's Association [Alzheimers Dement] 2024 Jun; Vol. 20 (6), pp. 4126-4146. Date of Electronic Publication: 2024 May 12.
DOI: 10.1002/alz.13828
Abstrakt: 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.
(© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
Databáze: MEDLINE
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