Brain plasmin enhances APP alpha-cleavage and A beta degradation and is reduced in Alzheimer's disease brains

The proteolytic processing of amyloid precursor protein (APP) has been link ed to sphingolipid-cholesterol microdomains (rafts). However, the raft prot eases that may be involved in APP cleavage have not yet been identified. In this work we present evidence that the protease plasmin is restricted to r afts of cultured hippocampal neurons. We also show that plasmin increases t he processing of human APP preferentially at the alpha -cleavage site, and efficiently degrades secreted amyloidogenic and non-amyloidogenic APP fragm ents. These results suggest that brain plasmin plays a preventive role in A PP amyloidogenesis. Consistently, we show that brain tissue from Alzheimer' s disease patients contains reduced levels of plasmin, implying that plasmi n downregulation may cause amyloid plaque deposition accompanying sporadic Alzheimer's disease.