Implications of the human serine protease HtrA1 in Alzheimer's disease

HtrA家族代表了一类新的低聚丝氨酸蛋白酶，其中催化结构域与c端PDZ结构域相结合。这些蛋白质广泛保守，存在于大多数生物体中。虽然两种细菌htra的生理功能已经得到了很好的研究，但人类htra的确切功能尚不清楚。我们之前的研究表明，人类HtrA1可能参与淀粉样蛋白前体蛋白（APP）的加工。最近的数据显示，HtrA1启动子的遗传变异导致阿尔茨海默病的早期发病和患者神经斑块形成的增加。此外，HtrA1被鉴定为寻找已久的tau蛋白酶，它将tau蛋白中参与缠结形成的元素切割成小肽。因此，我们希望开展旨在精确描述HtrA1参与APP和tau代谢以及阿尔茨海默病的研究。为此目的，将结合体外生物化学、晶体学、细胞生物学和体内模型。此外，我们将寻找激活蛋白酶的肽或小分子，并确定其效力和治疗相关性。

The HtrA family represents a new class of oligomeric serine proteases in which a catalytic domain is combined with C-terminal PDZ domains. These proteins are widely conserved and are present in most organisms. While the physiological functions of two bacterial HtrAs are well studied, the precise functions of human HtrAs are not understood. Our previous work suggested that human HtrA1 might be involved in amyloid precursor protein (APP) processing. Recent data revealed that a genetic variance in the HtrA1 promoter causes early onset of Alzheimer s disease and an increase in neuritic plaque formation in patients. In addition, HtrA1 was identified as the long sought tau protease cleaving the elements of tau that are involved in tangle formation into small peptides. We therefore wish to initiate studies aiming at a precise characterisation of the involvement of HtrA1 in APP and tau metabolism and thus in Alzheimer s disease. For this purpose a combination of in vitro biochemistry, crystallography, cell biology and in vivo models will be used. In addition, we will seek to identify peptides or small molecules activating the protease and to determine their potency and therapeutic relevance.