Identification of alternative BACE1 and BACE2 substrates and affected pathways in neuroinflammation and Alzheimer's disease

Alzheimer's disease (AD) is the most common neurodegenerative disease in humans, affecting millions of people worldwide. Currently, there is no cure for AD or treatment that can mitigate the disease process. However, recent research has revealed beta-site amyloid precursor cleaving enzyme 1 (BACE1), as a promising therapeutic target for AD. BACE1 is the protease that cuts Amyloid Precursor Protein (APP) at the beta-site. This cleavage of APP triggers a second cleavage, which releases the Amyloid-beta fragment. Accumulation of Amyloid-beta is believed to initiate the catastrophic cascade of events that lead to the onset of AD. Animal data suggest that BACE1 inhibition prevents Amyloid-beta formation and may be well tolerated, and therefore, BACE1 is considered one of the most promising drug targets for preventing and mitigating AD. However, recent work has revealed that APP is not the only substrate of BACE1. Consequently, drug-targeting strategies will modulate processing of both known and unknown substrates, any one of which may lead to undesirable or deleterious side effects. Therefore, the identification of all BACE1 substrates is necessary to predict and understand side effects of BACE1 inhibitors. Pitter Huesgen is working to identify new substrates and pathways modified by BCAE1 and the related enzyme, BACE2. His results will provide essential information on the complex physiological functions of BACE1 and BACE2 and their roles in the pathogenesis of AD, and help to predict side effects of BACE1 inhibitors, which will ultimately decide if BACE1 inhibition is a viable treatment strategy for AD.