Model studies have shown that in mice, ovariectomy increases amyloid B (AB) peptide levels, while ovariectomy followed by estrogen replacement lowers the concentration of AB 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 AB peptide clearance in the brain. We thus postulate that the effect of the estrogen depletion in raising AB peptide levels and estrogen replacement in lowering AB 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 AB 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 AB 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 AB 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 knockout mouse, and the J20 mouse crossed with an estrogen receptor knockout mouse. These experiments will establish whether the estrogen dependent decreases in AB peptide levels is a result of the estrogen dependent increased in neprilysin activity and whether an estrogen receptor dependent mechanism is responsible for reported effect of androgen depletion increasing AB peptide levels and androgen replacement lowering AB peptide levels is due to androgen effects on neprilysin. ? ? Using mouse models we will determine whether steroid hormone mediated effects on AB 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 Alzheimer's disease. ? ?
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