ABI3对阿尔茨海默病小胶质细胞吞噬功能调控及机制研究

Recently, it was firstly found that a rare coding variant in Abl-interactor 3 (ABI3) was associated with the risk for Alzheimer's disease (AD). However, the action of ABI3 in AD is unclear. Our Previous research has detected that ABI3 is mainly expressed in the microglia of the animal model with AD. It have been also detected that the expression of ABI3 is higher in the model mice with AD than the control mice and the levels of ABI3 mRNA are positively correlated with the levels of beta-amyloid (Aβ). ABI3 is involved in the regulation of actin cytoskeleton. The Aβ phagocytosis of the microglia in AD brains is depended on actin polymerization and cytoskeleton rearrangement. Therefore, we propose a hypothesis: ABI3 may be involved in AD through regulating the phagocytosis of the microglia. Using a mice model of AD, we intend to employ the gene silencing/overexpression technique to regulate the expression of ABI3 and investigate the effects of ABI3 in regulating the phagocytosis of the microglia in AD in vitro and vivo. By adopting the protein interactions, bioinformatics, molecular genetics and other modern biotechnology and so on, we will find the target proteins which interact with ABI3 in the microglia in AD and investigate the possible molecular mechanism by which ABI3 regulates the phagocytosis of microglia in AD. This study will provide new insights into the role of ABI3 in AD and highlight ABI3 as a potential therapeutic target for this disease.

近期研究首次发现Abl相互作用蛋白3（ABI3）基因的罕见编码变异位点与阿尔茨海默病（AD）发病相关，但ABI3参与AD发病的作用机制尚不清楚。我们前期利用AD动物模型检测发现ABI3主要表达于小胶质细胞，在AD中表达量升高，且与脑内β-淀粉样蛋白（Aβ）含量正相关。ABI3参与调控肌动蛋白细胞骨架，AD中小胶质细胞吞噬Aβ是通过肌动蛋白聚合促使细胞骨架重排来实现。由此推测ABI3可能调控小胶质细胞吞噬功能进而参与AD发病。为此，我们将利用AD小鼠模型，在细胞和动物水平采用基因沉默/过表达技术靶向调节ABI3表达，研究ABI3对小胶质细胞吞噬Aβ功能的影响；运用蛋白互作技术、生物信息学、分子遗传学等现代生物学技术寻找AD小胶质细胞中与ABI3相互作用的靶标蛋白，探讨ABI3调控AD小胶质细胞吞噬功能可能的分子机制。本研究将为探明ABI3参与AD的作用机制和寻找AD防治靶点提供新的理论依据。

近期研究首次发现Abl相互作用蛋白3（ABI3）基因的罕见编码变异位点与阿尔茨海默病（AD）发病相关。ABI3参与调控肌动蛋白细胞骨架，AD中小胶质细胞吞噬β-淀粉样蛋白（Aβ）是通过肌动蛋白聚合促使细胞骨架重排来实现。考虑到ABI3主要在小胶质细胞表达，且小胶质细胞在AD的病理进程中起十分重要的作用，在我们前期实验发现ABI3在APPswe/PS1dE9双转基因小鼠中表达量升高且与脑内Aβ含量相关的基础上，我们应用体内、外实验和APPswe/PS1dE9转基因AD小鼠模型研究发现:ABI3的上调是对Aβ的一种代偿性反应。靶向上调ABI3可以增强小胶质细胞对Aβ的吞噬能力，改善AD转基因小鼠脑内Aβ病理改变及空间学习记忆能力。而且，我们进一步发现ABI3可能通过与其相互作用的靶标蛋白磷酸二羟丙酮酰基转移酶蛋白（GNPAT）、促分裂原活化蛋白激酶激酶激酶激酶2（MAP4K2）来调控AD小胶质细胞的吞噬功能。本项目研究成果初步阐明了ABI3对AD小胶质细胞吞噬功能调控作用和可能的分子机制，为明确ABI3参与AD病理进程的作用机制提供了理论证据，为预防和治疗AD提供了新的途径和靶点。