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

点击翻译按钮获取中文摘要

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.