Copper Related Protein CUTA Regulates BACE1 Level And APP Processing

Alzheimer's disease(AD) is a progressive neurodegenerative disease characterized by neurofibrillary tangles(NFT) consisting of hyperphosphorylated tau protein and amyloid plaques consisting ofβ-amyloid peptides(Aβ).Aβ,which plays a crucial role in AD pathogenesis/progression,is derived from sequential cleavages ofβ-amyloid precursor protein(APP) byβ-secretase andγ-secretase.β-site APP cleaving enzyme 1(BACE1),which is considered to be the majorβ-secretase,is closely linked to AD.However,the regulation and functions of BACE1 are not fully elucidated yet.To further determine the regulation of BACE1,we used yeast two-hybrid system to screen for proteins interacting with BACE1 and identified one candidate protein,cutA divalent cation tolerance homolog of E.coli(CUTA). Our previous studies have shown exogenous interaction between BACE1 and CUTA. CUTA is a homolog of bacterial protein,copper tolerance A,involved in resistance to copper in bacteria.However,the specific function of CUTA in mammal is still unknown.In the present study,we confirmed the interaction between CUTA and endogenous BACE1 by co-immunoprecipitation.Furthermore,we found that CUTA can regulate BACE1 level and APP processing:overexpressin of CUTA decreased Aβgeneration and BACE1 protein level without affecting its mRNA level,whereas downregulation of endogenous CUTA increased both BACE1 and Aβlevels.Because copper is closely linked to AD and may be related to BACE1 and CUTA,we also studied the relationship among copper,BACE1,CUTA and APP processing.Our results showed that copper treatments increased BACE1 protein level,accompanied with increased secretion of CUTA and decreased level of intracellular CUTA in HEK293-Swedish cells.However,Aβlevel was not up-regulated by copper overload which may be due to enhanced non-amyloidogenic processing of APP.In addition,the effect of copper on BACE1 level can be inhibited by overexpression of CUTA.Our data suggest an important role for CUTA in regulating BACE1 and APP processing.Our results also imply a potential relationship among copper,CUTA,BACE1 and APP processing.