Estrogen reportedly influences neurogenesis (new neuron formation) and neuronal survival of progenitorcells in the adult female rat hippocampal dentate gyrus (DG). While 17beta-estradiol (E2) is believed to bethe estrogen subserving such functions, its little studied and largely ignored, natural steroisomer, 17alpha-E2may be the more important estrogen for the brain. This proposal tests the hypothesis that 17alpha-E2 andER-X, its plasma-membrane -associated receptor, and not the traditional 17beta-E2/nuclear ER-alpha andER-beta receptor systems, mediate the effects of estrogen on neurogenesis and neuronal survival. Thishypothesis is based on our observations that the en dogenous content of 17alpha-E2 i n the adulthippocampal DG is significantly higher than that of 17beta-E2 and that adult hippocampal progenitor cellshave high levels of 'ER-X', while deficient in ER-alpha and ER-beta. This suggests that 17alpha-E2 has acrucial role in the hippocampal DG throughout life. This proposal consists of a series of correlative andcomplementary in vitro and in vivo experiments to compare the roles of 17alpha-E2 and 17beta-E2 inneurogenesis and neuronal survival, following an ischemic stroke, of the progenitor cells of the hippocampalDG of variously-aged C57BL/6J and 129/SvEV intact and ovariectomized (OVX) female mice, and othergenotypes, including ER-alpha null, the aromatase knockout (ArKO) and transgenic Alsheimer's mice.Expression of ER-X in adult progenitor cells suggests that 17alpha-E2, its specific ligand, may havetherapeutic potential for aging and neurodegenerative disorders. Absent circulating 17alpha-E2 levels,17alpha-E2 and 'ER-X' are unlikely to be part of a classical endocrine hormone/receptor system but may besynthesized locally and have important autocrine/paracrine brain functions. The therapeutic challenge is todiscover how to stimulate and manipulate the endogenous progenitor cells, and how to make clinical use ofthe potential benefits of the elevated endogenous brain content of 17alpha-E2. The results will lead to drugdesign and therapeutic intervention without fear of undesirable peripheral effects mediated by ER-alpha orER-beta, with enormous implications for safer hormone replacement strategies at the menopause and in thetreatment of such neurodegenerative disorders as Alzheimer's disease and ischemic stroke, and psychiatricdisorders such as major depression which accompanies such disorders frequently.
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