Our previous data showed that neprilysin (NEP), a zinc metalloendopeptidase, which can degrade amyloid-beta peptide (Abeta) whose central nerve system accumulation is the primary cause of Alzheimer's disease (AD), responds to estrogen in the brain. Recently, it has been shown that the transcription of the neprilysin gene can be up regulated by progesterone, androgens, and glucocorticoids through two androgen response elements within the NEP gene--an androgen response region (ARR) and an androgen response element (ARE). Through a yeast report gene system, we now find that the ARR but not the ARE respond to estrogen. However, androgen could efficiently enhance the expression of the report gene mainly through ARE. Our results indicate that the decrease of NEP, caused by the decline of estrogen or androgen with aging, may be an important factor leading to Abeta accumulation and AD.