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

被引：7

作者：

Kotredes, Kevin P. ^{[1
]}

Pandey, Ravi S. ^{[2
]}

Persohn, Scott ^{[3
,4
]}

Elderidge, Kierra ^{[3
,4
]}

Burton, Charles P. ^{[3
,4
]}

Miner, Ethan W. ^{[3
,4
]}

Haynes, Kathryn A. ^{[5
]}

Santos, Diogo Francisco S. ^{[5
]}

Williams, Sean-Paul ^{[5
]}

Heaton, Nicholas ^{[5
]}

Ingraham, Cynthia M. ^{[4
]}

Lloyd, Christopher ^{[4
]}

Garceau, Dylan ^{[1
]}

O'Rourke, Rita ^{[1
]}

Herrick, Sarah ^{[1
]}

Rangel-Barajas, Claudia ^{[3
,6
]}

Maharjan, Surendra ^{[3
,4
,7
]}

Wang, Nian ^{[3
,4
,7
]}

Sasner, Michael ^{[1
]}

Lamb, Bruce T. ^{[3
,4
,6
]}

Territo, Paul R. ^{[3
,4
,8
]}

Sukoff Rizzo, Stacey J. ^{[5
]}

Carter, Gregory W. ^{[1
,2
,9
,10
]}

Howell, Gareth R. ^{[1
,9
,10
]}

Oblak, Adrian L. ^{[3
,4
,7
]}

机构：

[1] Jackson Lab, Bar Harbor, ME 04609 USA

[2] Jackson Lab Genom Med, Farmington, CT USA

[3] Indiana Univ Sch Med, Indianapolis, IN 46202 USA

[4] Stark Neurosci Res Inst, Indianapolis, IN USA

[5] Univ Pittsburgh Aging Inst, Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA

[6] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA

[7] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Indianapolis, IN USA

[8] Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, Indianapolis, IN USA

[9] Tufts Univ, Grad Sch Biomed Sci, Boston, MA USA

[10] Univ Maine, Grad Sch Biomed Sci & Engn, Orono, ME USA

来源：

ALZHEIMERS & DEMENTIA | 2024年 / 20卷 / 06期

关键词：

Alzheimer's disease; APOE4; genetics; high-fat diet; late-onset Alzheimer's disease; LOAD; MODEL-AD; TREM2; APOLIPOPROTEIN-E; BRAIN; RISK; NEURODEGENERATION; HYPERMETABOLISM; MICE;

D O I：

10.1002/alz.13828

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 (A beta). 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, A beta, neurodegeneration, neuroimaging, and multi-omics. RESULTS: By 18 months, LOAD2+HFD mice exhibited sex-specific neuron loss, elevated insoluble brain A beta 42, 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.

引用

页码：4126 / 4146

页数：21

共 45 条

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