Abstract
In a perimenopausal model of middle-aged rats, the astrocyte estrogen receptor-alpha (ERa): ER-beta (ERb) ratio increased with the onset of acyclicity (constant estrus, CE) in association with impaired neurotrophic responses to estradiol (E2). We report additional data on irregular cycling (IR) from this study of 9 month old perimenopausal subgroups. In particular, irregular cyclers (IR) also show increased ERa:ERb ratio in cerebral cortex astrocytes comparable to acyclic individuals in CE. In mixed glial cultures from these same cycling subgroups, the E2-dependent neurotrophic activity and glial fibrillary acidic protein (GFAP) repression by E2 were impaired in IR to the same degree as in CE-derived glia. The greater importance of cycling status than age during the perimenopause to astrocyte ERs are attributable to individual variations of the residual ovarian follicle pool, which determine the onset of acyclicity. The corresponding loss of E2-dependent GFAP repression and E2-dependent neurotrophic activity add further to the inverse relationship of GFAP expression and astrocyte neurotrophic activity across aging in both sexes. These findings are relevant to impairments of spatial learning and of hippocampal long-term potentiation during the onset of IR in middle-aged rats, and to perimenopausal factors mediating the higher risk of women for Alzheimer disease.
Highlights
Estrogen receptor-alpha (ERa) and estrogen receptor-beta (ERb) undergo age-related shifts in both sexes (Wilson et al, 2002; Wu et al, 2009; Arimoto et al, 2011, 2013; Arimoto, 2012; Foster, 2012)
Because glial fibrillary acidic protein (GFAP) is regulated by E2 through a classical promoter ERE that binds estrogen receptor-alpha (ERa) (Stone et al, 1998), we examined the role of ERs
To study perimenopausal changes associated with cycle lengthening, we used a mixed glia model (3:1 astrocytes; microglia), which had shown the same age changes of ERa, GFAP, and neurotrophic activity as enriched astrocytes in males (Arimoto et al, 2013)
Summary
Estrogen receptor-alpha (ERa) and estrogen receptor-beta (ERb) undergo age-related shifts in both sexes (Wilson et al, 2002; Wu et al, 2009; Arimoto et al, 2011, 2013; Arimoto, 2012; Foster, 2012). The elevated ERa:ERb in astrocyte cultures from aging males was manipulated by RNAi, which decreased GFAP (Rozovsky et al, 2005; Arimoto et al, 2013). Both E2 responses (GFAP repression and induction of neurotrophic activity) are lost during aging (Rozovsky et al, 2005; Arimoto et al, 2013). We describe primary glial cultures from the same groups for astrocyte GFAP expression in relation to neurotrophic activity
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