Estrogen mediates multiple functions in the brain through the interaction of estrogen receptor (ER)α and ERβ with a host of nuclear proteins that regulate specific gene transcription. We have identified ERAP 140, AIB 1, Trk A, Src, pCREB and CREB as ERβ interacting proteins in the mouse brain. Earlier we showed that the interaction of ERβ with ERAP 140 decreased whereas its expression increased with aging in the brain of female mice. Here we report that the pattern of interaction and expression is different in male mice as compared to females. The interaction of ERAP 140 with ERβ decreased in adult male mouse brain as compared to young and remained almost similar in old whereas its expression was higher in adult than young and old, which were almost similar. Further in silico secondary structure analysis by self-optimized prediction method alignment (SOPMA) and PSIPRED revealed that ERβ interacting proteins were rich in alpha helices and coils. Such findings might help to design ER modulators which can regulate specific functions of estrogen in the brain during aging and degenerative diseases.