HtrA2 interacts with A beta peptide but does not directly alter its production or degradation.

HtrA2/Omi is a mammalian mitochondrial serine protease homologous to the E. coli HtrA/DegP gene products. Recently, HtrA2/Omi was found to have a dual role in mammalian cells, acting as an apoptosis-inducing protein and being involved in maintenance of mitochondrial homeostasis. By screening a human brain cDNA library with A beta peptide as bait in a yeast two-hybrid system, we identified HtrA2/Omi as a binding partner of A beta peptide. The interaction between A beta peptide and HtrA2/Omi was confirmed by an immunoblot binding assay. The possible involvement of HtrA2/Omi in A beta peptide metabolism was investigated. In vitro peptide cleavage assays showed that HtrA2/Omi did not directly promote the production of A beta peptide at the beta/gamma-secretase level, or the degradation of A beta peptide. However, overexpression of HtrA2/Omi in K269 cells decreased the production of A beta40 and A beta42 by up to 30%. These results rule out the involvement of HtrA2/Omi in the etiology of Alzheimer's disease. However, the fact that overexpression of HtrA2/Omi reduces the generation of A beta40 and A beta42 suggests that it may play some positive role in mammalian cells.