INTRODUCTIONMODEL‐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.METHODSWe 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.RESULTSBy 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.DISCUSSIONThe 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.

中文翻译：

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表征独立于淀粉样蛋白和 tau 病理学的晚发性阿尔茨海默病小鼠模型的分子和突触特征

简介 MODEL-AD（晚发性阿尔茨海默病模型生物体开发和评估）正在创建和分发具有人性化、临床相关遗传风险因素的新型小鼠模型，以更准确地捕捉晚发阿尔茨海默病 (LOAD) 的轨迹和进展。通过结合载脂蛋白 E4 (APOE4)、Trem2*R47H 和人源化淀粉样蛋白-β (Aβ) 创建了 LOAD2 模型。小鼠接受对照饮食或高脂肪/高糖饮食（LOAD2+HFD）。我们评估了血浆和大脑中与疾病相关的结果指标，包括神经炎症、Aβ、神经变性、神经影像学和多组学。结果到 18 个月时，LOAD2+HFD 小鼠表现出性别特异性神经元损失、不溶性脑 Aβ42 升高、血浆神经丝轻链增加(NfL)，并改变与脂质代谢和突触功能相关的基因/蛋白质表达。影像学显示脑容量减少和神经血管解偶联。观察到获得基于触摸屏的认知任务的缺陷。讨论 LOAD2+HFD 小鼠的综合表征表明，该模型对于寻求了解淀粉样斑块和 tau 缠结之前或独立的 LOAD 的疾病轨迹和进展的临床前研究非常重要。 到 18 个月时，与对照小鼠（例如，喂食对照饮食 CD 的 LOAD2 小鼠）不同，LOAD2+HFD 小鼠的皮质神经元出现微妙但显着的损失，大脑中不溶性 Ab42 水平升高，血浆神经丝轻链增加（美国橄榄球联盟）。 转录组学和蛋白质组学显示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）和神经血管解偶联（PET/CT）与年龄相关的减少。 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。