Central Nervous System, Blood and Peripheral Inflammation, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
Department of Pharmaceutical Sciences and Medicines, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
Cells. 2022 Jan 1;11(1):137. doi: 10.3390/cells11010137.
The prevalence of Alzheimer's disease (AD), the most common cause of age-associated dementia, is estimated to increase over the next decades. Evidence suggests neuro-immune signaling deregulation and risk genes beyond the amyloid-β (Aβ) deposition in AD pathology. We examined the temporal profile of inflammatory mediators and microglia deactivation/activation in the brain cortex and hippocampus of 3xTg-AD mice at 3- and 9-month-old. We found upregulated APP processing, decreased expression of , , , and and increased miR-146a in both brain regions in 3-month-old 3xTG-AD mice, suggestive of a restrictive regulation. Enhanced , , , , and were only present in the hippocampus of 9-month-old animals, though elevation of and reduction of miR-146a and miR-124 were common features in the hippocampus and cortex regions. miR-155 increased early in the cortex and later in both regions, supporting its potential as a biomarker. Candidate downregulated target genes by cortical miR-155 included , and at 3 months and , and at 9 months, which are implicated in cell survival, but also in Aβ pathology and microglia/astrocyte dysfunction. Data provide new insights across AD state trajectory, with divergent microglia phenotypes and inflammatory-associated features, and identify critical targets for drug discovery and combinatorial therapies.
阿尔茨海默病（AD）是最常见的与年龄相关的痴呆症，其患病率预计在未来几十年内会增加。有证据表明，AD 病理除了淀粉样蛋白-β（Aβ）沉积之外，还存在神经免疫信号失调和风险基因。我们在 3 个月和 9 个月大的 3xTg-AD 小鼠的大脑皮层和海马体中研究了炎症介质和小胶质细胞失活/激活的时间进程。我们发现，在 3 个月大的 3xTG-AD 小鼠的两个脑区中，APP 处理上调， 、 、 、 和 的表达下调，miR-146a 增加，表明存在限制调节。在 9 个月大的动物的海马体中仅存在增强的 、 、 、 和 ，尽管 升高和 miR-146a 和 miR-124 减少是海马体和皮层区域的共同特征。miR-155 在皮层中早期增加，在两个区域中晚期增加，支持其作为生物标志物的潜力。皮层 miR-155 下调的候选靶基因包括 3 个月时的 、 和 ，以及 9 个月时的 、 和 ，这些基因涉及细胞存活，但也与 Aβ 病理和小胶质细胞/星形胶质细胞功能障碍有关。这些数据为 AD 状态轨迹提供了新的见解，具有不同的小胶质细胞表型和炎症相关特征，并确定了药物发现和联合治疗的关键靶标。
