PDF(Pubmed)
Abstract：
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.
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.
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.
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.
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.
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.
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.
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.
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.
摘要：
背景：MODEL-AD（晚期阿尔茨海默病的模型生物体开发和评估）正在创建和分发具有人源化的新型小鼠模型，临床相关的遗传危险因素，以更准确地捕获晚发性阿尔茨海默病（LOAD）的轨迹和进展。
方法：我们通过结合载脂蛋白E4（APOE4）创建了LOAD2模型，Trem2*R47H,和人源化淀粉样蛋白-β(Aβ)。对小鼠进行对照饮食或高脂肪/高糖饮食(LOAD2+HFD)。我们评估了血浆和大脑中疾病相关的结局指标，包括神经炎症，Aβ,神经变性,神经影像学,和多元组学。
结果：到18个月，LOAD2+HFD小鼠表现出性别特异性神经元丢失，不溶性脑Aβ42升高，血浆神经丝轻链（NfL）增加，以及与脂质代谢和突触功能相关的基因/蛋白质表达改变。影像学显示脑容量和神经血管解偶联减少。观察到在获取基于触摸屏的认知任务方面的缺陷。
结论：LOAD2+HFD小鼠的综合特征表明，该模型对于寻求了解LOAD在淀粉样蛋白斑和tau缠结之前或独立于淀粉样蛋白斑和tau缠结之前的疾病轨迹和进展的临床前研究非常重要。
结论：到18个月，与对照小鼠不同(例如，LOAD2小鼠饲喂对照饮食，CD),LOAD2+HFD小鼠在皮质中表现出微妙但显著的神经元损失，大脑中不溶性Ab42的水平升高，和增加的血浆神经丝轻链(NfL)。转录组学和蛋白质组学显示了与多种疾病相关过程（包括脂质代谢和突触功能）相关的基因/蛋白质的变化。体内成像显示大脑区域体积（MRI）和神经血管解耦（PET/CT）的年龄依赖性减少。LOAD2+HFD小鼠在获取基于触摸屏的认知任务方面也表现出缺陷。
方法：我们通过结合载脂蛋白E4（APOE4）创建了LOAD2模型，Trem2*R47H,和人源化淀粉样蛋白-β(Aβ)。对小鼠进行对照饮食或高脂肪/高糖饮食(LOAD2+HFD)。我们评估了血浆和大脑中疾病相关的结局指标，包括神经炎症，Aβ,神经变性,神经影像学,和多元组学。
结果：到18个月，LOAD2+HFD小鼠表现出性别特异性神经元丢失，不溶性脑Aβ42升高，血浆神经丝轻链（NfL）增加，以及与脂质代谢和突触功能相关的基因/蛋白质表达改变。影像学显示脑容量和神经血管解偶联减少。观察到在获取基于触摸屏的认知任务方面的缺陷。
结论：LOAD2+HFD小鼠的综合特征表明，该模型对于寻求了解LOAD在淀粉样蛋白斑和tau缠结之前或独立于淀粉样蛋白斑和tau缠结之前的疾病轨迹和进展的临床前研究非常重要。
结论：到18个月，与对照小鼠不同(例如，LOAD2小鼠饲喂对照饮食，CD),LOAD2+HFD小鼠在皮质中表现出微妙但显著的神经元损失，大脑中不溶性Ab42的水平升高，和增加的血浆神经丝轻链(NfL)。转录组学和蛋白质组学显示了与多种疾病相关过程（包括脂质代谢和突触功能）相关的基因/蛋白质的变化。体内成像显示大脑区域体积（MRI）和神经血管解耦（PET/CT）的年龄依赖性减少。LOAD2+HFD小鼠在获取基于触摸屏的认知任务方面也表现出缺陷。
