Microglia, the resident immune cells of the brain, have recently emerged as key players in Alzheimer Disease (AD) pathogenesis, but their roles in AD remain largely elusive and require further investigation. Microglia functions are readily altered when isolated from their brain environment, and microglia reporter mice thus represent valuable tools to study the contribution of these cells to neurodegenerative diseases such as AD. The CX3CR1+/eGFP mice is one of the most popular microglia reporter mice, and has been used in numerous studies to investigate in vivo microglial functions, including in the context of AD research. However, until now, the impact of CX3CR1 haplodeficiency on the typical features of Alzheimer Disease has not been studied in depth. To fill this gap, we generated APPswe/PSEN1dE9:CX3CR1+/eGFP mice and analyzed these mice for Alzheimer's like pathology and neuroinflammation hallmarks. More specifically, using robust multifactorial statistical and multivariate analyses, we investigated the impact of CX3CR1 deficiency in both males and females, at three typical stages of the pathology progression: at early stage when Amyloid-β (Aβ) deposition just starts, at intermediate stage during Aβ accumulation phase and at more advanced stages when Aβ plaque number stabilizes. We found that CX3CR1 haplodeficiency had little impact on the progression of the pathology in the APPswe/PSEN1dE9 model and demonstrated that the APPswe/PSEN1dE9:CX3CR1+/eGFP line is a relevant and useful model to study the role of microglia in Alzheimer Disease. In addition, although Aβ plaques density is higher in females compared to age-matched males, we show that their glial reaction, inflammation status and memory deficits are not different.

中文翻译：

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分析雄性和雌性 APPswe/PSEN1dE9 小鼠在阿尔茨海默病进展过程中的 CX3CR1 单倍体缺陷

小胶质细胞是大脑的常驻免疫细胞，最近已成为阿尔茨海默病 (AD) 发病机制的关键参与者，但它们在 AD 中的作用在很大程度上仍然难以捉摸，需要进一步研究。当从大脑环境中分离出来时，小胶质细胞的功能很容易改变，因此小胶质细胞报告小鼠代表了研究这些细胞对 AD 等神经退行性疾病的贡献的有价值的工具。CX3CR1+/eGFP 小鼠是最受欢迎的小胶质细胞报告小鼠之一，已被用于研究体内小胶质细胞功能的众多研究，包括在 AD 研究的背景下。然而，到目前为止，尚未深入研究 CX3CR1 单倍体缺陷对阿尔茨海默病典型特征的影响。为了填补这一空白，我们生成了 APPswe/PSEN1dE9：CX3CR1+/eGFP 小鼠并分析这些小鼠的阿尔茨海默病样病理学和神经炎症特征。更具体地说，使用稳健的多因素统计和多变量分析，我们在病理进展的三个典型阶段调查了 CX3CR1 缺乏对男性和女性的影响：在淀粉样蛋白-β (Aβ) 沉积刚刚开始的早期阶段，在中间阶段在 Aβ 积累阶段和 Aβ 斑块数量稳定的更高级阶段。我们发现 CX3CR1 单倍体缺陷对 APPswe/PSEN1dE9 模型中的病理学进展几乎没有影响，并证明 APPswe/PSEN1dE9:CX3CR1+/eGFP 系是研究小胶质细胞在阿尔茨海默病中作用的相关且有用的模型。此外，虽然与年龄匹配的男性相比，女性的 Aβ 斑块密度更高，