Neuroprotective effects of estradiol in hippocampal neurons and glia of middle age mice

SummaryDuring aging the hippocampus experiences structural, molecular, and functional alterations. Protection from age-related disorders is provided by several factors, including estrogens. Since aging defects start at middle age, we studied if 17 β-estradiol (E2) protected the hippocampus at this age period. Middle age (10–12 month old) male C57Bl/6 mice were implanted sc with E2 (15 μg) or cholesterol pellets. Ten days afterwards they received bromodeoxyuridine (BrdU) 4 and 2 h before killing to study cell proliferation in the dentate gyrus (DG). A pronounced depletion of BrdU+cells in the DG was found in cholesterol-treated middle age mice, accompanied by astrocytosis, and by neuronal loss in the hilus. Middle age mice receiving E2 showed increased number of BrdU+cells while the other parameters were remarkably attenuated. When steroid treatment was prolonged for 2 months to study migration of cells in the granular layer of the DG, cell migration was unaffected by E2. However, E2-treated middle age mice presented higher cell density and increased staining for doublecortin, a marker for differentiating neurons. Thus, from the three basic steps of adult neurogenesis (proliferation, migration, and differentiation), E2 stimulated progenitor proliferation—even after long exposure to E2 studied by Ki67 immunocytochemistry—and differentiation towards a neuronal lineage. This result, in conjunction with recovery from other aging indicators as increased deposits of the aging pigment lipofuscin in DG cells, loss of hilar neurons and astrocytosis supports a wide range protection of hippocampal function of middle age mice by estrogenic hormones.