Alzheimer's disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and result from multiple etiologic factors, including environmental, genetic, and metabolic factors, whereas FAD is caused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP) genes. A commonly used animal model for AD is the 3xTg-AD transgenic mouse model, which harbors mutated presenilin 1, APP, and tau genes and thus represents a model of FAD. There is an unmet need in the field to characterize animal models representing different AD mechanisms, so that potential drugs for SAD can be evaluated preclinically in these animal models. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study, we compared the non-cognitive and cognitive behaviors as well as biochemical and immunohistochemical alterations between the icv-STZ mouse and the 3xTg-AD mouse. We found that both mouse models showed increased exploratory activity as well as impaired learning and spatial memory. Both models also demonstrated neuroinflammation, altered synaptic proteins and insulin/IGF-1 (insulin-like growth factor-1) signaling, and increased hyperphosphorylated tau in the brain. The most prominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the 3xTg-AD mouse it was elevation of hyperphosphorylated tau. These observations demonstrate the behavioral and neuropathological similarities and differences between the icv-STZ mouse and the 3xTg-AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.

译文

阿兹海默症 (AD) 可分为散发性AD (SAD) 和家族性AD (FAD)。大多数AD病例是散发性的,是由多种病因引起的,包括环境,遗传和代谢因素,而FAD是由presenilins或淀粉样蛋白-β (a β) 前体蛋白 (APP) 基因突变引起的。AD的常用动物模型是3xTg-AD转基因小鼠模型,该模型具有突变的早老蛋白1,APP和tau基因,因此代表了FAD模型。在本领域中,对代表不同AD机制的动物模型进行表征的需求尚未得到满足,因此可以在这些动物模型中进行临床前评估SAD的潜在药物。通过脑室内 (icv) 施用链脲佐菌素 (STZ) 生成的小鼠模型,即icv-stz小鼠,显示了SAD的许多方面。在这项研究中,我们比较了icv-stz小鼠和3xTg-AD小鼠之间的非认知和认知行为以及生化和免疫组织化学改变。我们发现,两种小鼠模型都显示出增加的探索活动以及受损的学习和空间记忆。两种模型还显示了神经炎症,突触蛋白和胰岛素/IGF-1 (胰岛素样生长因子-1) 信号的改变,以及大脑中过度磷酸化的tau增加。Icv-stz小鼠中最突出的大脑异常是神经炎症,而3xTg-AD小鼠则是过度磷酸化的tau升高。这些观察结果证明了icv-stz小鼠和3xTg-AD小鼠模型之间的行为和神经病理学异同,并将有助于指导使用这两种小鼠模型开发AD药物的未来研究。

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