Lyzl4参与小胶质细胞免疫炎症调控及阿尔茨海默症发生发展的机制研究

阿尔茨海默症（AD）是一种影响广泛的神经退行性疾病。AD早期，小胶质细胞激活后，释放炎症介质，促发神经免疫反应，导致疾病的进展和加重，但其潜在的细胞和分子机制尚不清楚。我们分离不同月龄的APPswe/PS1ΔE9 AD模型小鼠脑组织中的小胶质细胞，进行了转录组测序。发现在不同时间点的AD小鼠的小胶质细胞中，Lyzl4的表达水平均增高，与疾病进展趋势一致，Aβ1-42处理小胶质细胞模型可诱导Lyzl4表达升高。Lyzl4的升高促进了小胶质细胞中对Aβ的清除作用，提示Lyzl4可能参与Aβ诱导的AD样病理过程。本项目拟在前期工作基础上，以Lyzl4为研究目标，在细胞和动物模型中，明确A-beta诱导Lyzl4升高的分子机制以及Lyzl4影响小胶质细胞清除Aβ能力的机制；并在AD模型动物中进一步明确Lyzl4对免疫微环境的影响以及对小鼠AD进程的作用，为AD的发生发展机制提供新的线索和证据。

Alzheimer’s disease (AD) is a kind of neurodegenerative disease. At the early stage of AD, microglia is activated and neuroinflammation is induced, which may accelerate AD progression. However, the molecular mechanisms are still not clear yet. In our previous study, we use APPswe/PS1ΔE9 as an AD mouse model. Microglia from different-age brains were isolated by FACS for deep sequencing. Lyzl4 was higher expressed than controls at almost all time points, which is consistent with the AD progress. In vitro microglia cultures, Aβ1-42 could induce Lyzl4 increase. The overexpression of Lyzl4 in microglia promoted Aβ1-42 clearance by microglia. All the data indicated that Lyzl4 may be important in AD pathogenesis. In this study, we will elucidate the mechanism about A-beta-induced Lyzl4 expression and Lyzl4-regulated brain micro and immune environment. In AD mouse model, APPswe/PS1ΔE9 double transgeneic mice, Lyzl4 will be over-expressed or knocked-out for further understanding the regulatory role of Lyzl4 in AD pathogenesis. Based on the above results, we will try to understand the mechanism of Lyzl4-microglia-neuroinflammation affecting A-beta-related neuronal apoptosis and know more about AD pathogenesis.