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

Summary 

During 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 (15μg) or cholesterol pellets. Ten days afterwards they received bromodeoxyuridine (BrdU) 4 and 2h 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.

Keywords: Brain aging, Dentate gyrus, Neurogenesis, Estradiol, Neuroprotection, 5-bromo-2′-deoxyuridine (BrdU), Glial fibrillary acidic protein (GFAP), Hilar neurons, Lipofuscin, doublecortin, Ki67

Abbreviations: E₂, 17β estradiol, BrdU, bromodeoxyuridine, DG, dentate gyrus, SGZ, subgranular zone, DCX, doublecortin, GCL, granular cell layer, HPA, hypothalamic–pituitary–adrenal, GFAP, glial fibrillary acidic protein, MA, middle age, chol, cholesterol