Sustained brain chronic inflammation in Alzheimer’s disease (AD) includes glial cell activation, an increase in cytokines and chemokines, and lipid mediators (LMs), concomitant with decreased pro-homeostatic mediators. The inflammatory response at the onset of pathology engages activation of pro-resolving, pro-homeostatic LMs followed by a gradual decrease. We used an APP knock-in (App KI) AD mouse that accumulates β-amyloid (Aβ) and presents cognitive deficits (at 2 and 6 months of age, respectively) to investigate LMs, their precursors, biosynthetic enzymes and receptors, glial activation, and inflammatory proteins in the cerebral cortex and hippocampus at 2-, 4-, 8- and 18-month-old in comparison with wild-type (WT) mice. We used LC-mass-spectrometry and MALDI molecular imaging to analyze LMs and phospholipids, and immunochemistry for proteins. Our results revealed an age-specific lipid and cytokine profile, and glial activation in the App KI mice. Despite an early onset of Aβ pathology, pro-inflammatory and pro-resolving LMs were prominently increased only in the oldest age group. Furthermore, the LM biosynthetic enzymes increased, and their receptor expression decreased in the aged App KI mice. Arachidonic acid (AA)-containing phospholipid molecular species were elevated, correlating with decreased cPLA2 activity. MALDI molecular imaging depicted differential distribution of phospholipids according to genotype in hippocampal layers. Brain histology disclosed increased microglia proliferation starting from young age in the App KI mice, while astrocyte numbers were enhanced in older ages. Our results demonstrate that the brain lipidome is modified preferentially during aging as compared to amyloid pathology in the model studied here. However, alterations in phospholipids signal early pathological changes in membrane composition.

中文翻译：

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阿尔茨海默病APP敲入小鼠模型中脑磷脂和生物活性脂质的年龄相关变化

阿尔茨海默病 (AD) 中持续的脑慢性炎症包括神经胶质细胞激活、细胞因子和趋化因子以及脂质介质 (LM) 的增加，同时伴随着促稳态介质的减少。病理开始时的炎症反应会激活促消退、促稳态的 LM，然后逐渐减少。我们使用 APP 敲入 (App KI) AD 小鼠来研究 LMs、它们的前体、生物合成酶和受体、神经胶质激活，以及与野生型 (WT) 小鼠相比，2、4、8 和 18 个月大的大脑皮层和海马中的炎症蛋白。我们使用 LC 质谱和 MALDI 分子成像来分析 LM 和磷脂，以及蛋白质的免疫化学。我们的结果揭示了 App KI 小鼠的年龄特异性脂质和细胞因子谱以及神经胶质激活。尽管 Aβ 病理学发病较早，但仅在年龄最大的年龄组中，促炎性和促消退性 LMs 显着增加。此外，LM 生物合成酶增加，其受体表达在老年 App KI 小鼠中降低。含花生四烯酸 (AA) 的磷脂分子种类升高，与 cPLA2 活性降低有关。MALDI 分子成像根据海马层中的基因型描绘了磷脂的差异分布。脑组织学显示，App KI 小鼠从年轻时开始小胶质细胞增殖增加，而星形胶质细胞数量在老年时增加。我们的结果表明，与此处研究的模型中的淀粉样蛋白病理相比，大脑脂质组在衰老过程中优先被修改。然而，磷脂的改变预示着膜成分的早期病理变化。