线粒体内Aβ可导致线粒体功能紊乱，而前序蛋白酶(PreP)是目前发现线粒体内Aβ的唯一降解酶，其活性将决定线粒体内Aβ的含量，但调节机制未明。我们的预实验结果显示二甲基精氨酸二甲胺水解酶(DDAH-1)可明显减低线粒体内Aβ的含量，并证实其主要表达于线粒体外膜。那么位于线粒体的DDAH-1是否通过对PreP活性的调节影响线粒体内Aβ的含量，其具体机制如何呢？为此，我们提出如下假说：DDAH-1可能通过1）上调线粒体内一氧化氮浓度从而增加线粒体内蛋氨酸硫氧化物还原酶表达；2）下调线粒体内非对称性二甲基精氨酸所增加的ROS含量，最终降低PreP的氧化修饰水平，维持其降解线粒体内Aβ的活性。我们将在体外研究中采用一系列分子生物学方法，明确DDAH-1调控线粒体内Aβ含量的具体分子机制，并进一步在DDAH-1基因敲除大鼠模型中予以验证。本研究试图从调控线粒体内Aβ这一角度，为AD的诊疗提供新靶点。

Mitochondrial beta-amyloid polypeptide (Aβ) is an important factor leading to mitochondrial dysfunction.Presequence protease (Prep) is the only enzyme to degrade Aβ in mitochondria found so far. Its activity will determine the content of Aβ in mitochondria, but its regulation mechanism is still unclear. Our preliminary results showed that dimethylarginine dimethylamine hydrolase-1 (DDAH-1), mainly expressed in the outer membrane of mitochondria, could significantly reduce the content of Aβ in mitochondria. Then, it needs further research whether DDAH-1 regulate the content of Aβ in mitochondria through PreP. We propose the following hypothesis: DDAH-1 may reduce oxidative modification of PreP and maintain its activity of degrading Aβ in mitochondria through 1）the enhanced activity of methionine sulfoxide reductases by up-regulating local nitric oxide concentration in mitochondria and 2) the down-regulating content of ROS induced by asymmetric dimethylarginine in mitochondria. To verify this hypothesis, we will use a series of molecular biological methods in vitro to clarify the specific molecular mechanism of DDAH-1 regulating the content of Aβ in mitochondria, and further validate it in the DDAH-1 gene knockout rat model. This study attempts to provide a new target for the diagnosis and treatment of AD from the perspective of regulating Aβ in mitochondria.