Estrogen, Androgen, Neprilysin and Amyloid Peptides

Model studies have shown that in mice, ovariectomy increases amyloid ~ (A~) peptide levels, while ovariectomy followed by estrogen replacement lowers the concentration of A~ peptides to normal or below normal levels. We recently found that ovariectomy in rats leads to a decrease in the activity of the peptidase neprilysin, and that ovariectomy followed by estrogen replacement increases neprilysin gene transcription and neprilysin enzyme activity in the brain. Neprilysin has been shown to be the major, or one of the major, enzymes involved in A~ peptide clearance in the brain. We thus postulate that the effect of estrogen depletion in raising A~ peptide levels and estrogen replacement in lowering A~ peptide levels occurs, at least in part, as a result of estrogen effects on neprilysin activity. Similarly, it has recently been shown that gonadectomy increases A~ peptide levels in rats, and androgen replacement reverses this effect. Since the neprilysin gene is also regulated by androgens, we speculate that the effect of gonadectomy and androgen replacement on A~ peptide levels is also mediated through effects on the neprilysin gene. Two specific aims are proposed to test this hypothesis: (1) we will compare the effect of estrogen in reducing A~ peptide levels in mice expressing a mutant human amyloid precursor protein containing the Swedish and Indiana mutations (J20 mouse line) to the effect of estrogen in the J20 mouse crossed with a neprilysin knock-out mouse, and the J20 mouse crossed with an estrogen receptor knock-out mouse. These experiments will establish whether the estrogen dependent decreases in A~ peptide levels is a result of the estrogen dependent increases in neprilysin activity and whether an estrogen receptor dependent mechanism is responsible for both the decrease in A~ peptide levels and the increase in neprilysin activity and (2) to determine if the reported effect of androgen depletion increasing A~ peptide levels and androgen replacement lowering A~ peptide levels is due to androgen effects on neprilysin. Using mouse models we will determine whether steroid hormone mediated effects on A~ peptide levels are a result of their affects on neprilysin activity and whether steroid hormones or their selective receptor modulators can serve as a target for the development of drugs for the prevention of AD.