Wu Yixing, Cleverley Karen, Wiseman Frances K
UK Dementia Research Institute at University College London, London, United Kingdom.
UCL Queen Square Institute of Neurology, Queen Square, London, United Kingdom.
PLoS One. 2025 Jan 22;20(1):e0316822. doi: 10.1371/journal.pone.0316822. eCollection 2025.
Down syndrome, resulting from trisomy of human chromosome 21, is a common form of chromosomal disorder that results in intellectual disability and altered risk of several medical conditions. Individuals with Down syndrome have a greatly increased risk of Alzheimer's disease (DSAD), due to the presence of the APP gene on chromosome 21 that encodes the amyloid-β precursor protein (APP). APP can be processed to generate amyloid-β, which accumulates in plaques in the brains of people who have Alzheimer's disease and is the upstream trigger of disease. Cathepsin B has potential roles in both APP processing and amyloid-β degradation and has been suggested to contribute to amyloid-β accumulation. An endogenous inhibitor of Cathepsin B, Cystatin B (CSTB), is encoded on chromosome 21. The abundance of this protein is increased in the brains of individuals with DSAD, which may be associated with a decrease in Cathepsin B activity compared to individuals who have Alzheimer's disease in the general population. Whether targeting CSTB can modulate Cathepsin B activity in the context of trisomy of chromosome 21 is unclear. Here we test if reducing CSTB can alter Cathepsin B activity in a mouse and a cellular model of trisomy of chromosome 21. We find that reducing CSTB abundance increases Cathepsin B activity in disomic controls but not in the presence of trisomy of chromosome 21. These findings offer new insights into the role of CSTB in regulating Cathepsin B activity.
唐氏综合征由人类21号染色体三体性引起，是一种常见的染色体疾病，会导致智力残疾并改变多种疾病的患病风险。唐氏综合征患者患阿尔茨海默病（DSAD）的风险大幅增加，这是因为21号染色体上存在编码淀粉样前体蛋白（APP）的APP基因。APP可被加工生成淀粉样β蛋白，该蛋白会在阿尔茨海默病患者大脑中形成斑块堆积，是疾病的上游触发因素。组织蛋白酶B在APP加工和淀粉样β蛋白降解过程中都具有潜在作用，并且有人认为它会促使淀粉样β蛋白积累。组织蛋白酶B的内源性抑制剂胱抑素B（CSTB）由21号染色体编码。在DSAD患者大脑中，这种蛋白质的丰度会增加，与一般人群中的阿尔茨海默病患者相比，这可能与组织蛋白酶B活性降低有关。在21号染色体三体的情况下，靶向CSTB是否能调节组织蛋白酶B的活性尚不清楚。在这里，我们测试了在21号染色体三体的小鼠和细胞模型中，降低CSTB是否能改变组织蛋白酶B的活性。我们发现，降低CSTB丰度会增加二体对照中的组织蛋白酶B活性，但在存在21号染色体三体的情况下则不会。这些发现为CSTB在调节组织蛋白酶B活性中的作用提供了新的见解。
