Age-Related Memory Impairment Associated With Decreased Endogenous Estradiol in the Hippocampus of Female Rats

Abstract

It is widely known that not only the gonadal estradiol (E2) but also hippocampal E2 plays an essential role in memory process. However, the role of hippocampal E2-enhanced memory mechanism during aging is largely unknown. The aim of the present study was to investigate the effect of age on E2 concentration, the expression level of its receptors, and key steroidogenic enzymes in hippocampus. We also investigated the effect of microglia activation on E2 synthesis in hippocampal neurons. The results showed that serum E2 was higher in 19-month-old (aged) rats, which exhibited spatial memory decline in the Morris water maze (MWM) test when compared to the younger rats. Hence, serum E2 may not be associated with the reduced spatial memory performance in aging. In contrast, the level of E2 and the expressions of its receptors were significantly decreased in hippocampus of aged female rat compared to younger females. Furthermore, the expressions of key hippocampal steroidogenic enzymes, steroidogenic acute regulatory protein (StAR), and cytochrome P450 (P450) also significantly decreased with age, which resulted in lower hippocampal E2 levels. In addition, we found that the microglia of aged brain highly expressed interleukin 6 (IL-6), which directly inhibited E2 synthesis in hippocampal neurons via suppression of P450 synthesis. Taken together, we summarized that the microglia-derived IL-6 inhibited hippocampal E2 synthesis in aged rats which, in turn, contributed to the deficit of spatial memory performance.

Differential effects of sex on longitudinal patterns of cognitive decline in Parkinson’s disease

“…Not only have oestrogens been found to play a role in dopaminergic neurodegeneration in PD, but the hormone has been found to have favourable effects on neuroinflammation, oxidative stress and iron metabolism within the context of PD [41]. Furthermore, sex differences in microglial and astrocytic cells, such as their heightened sensitivity to inflammatory stimuli [42][43][44] and their anatomical distribution [45,46], have been postulated to mediate sex differences in cognition and memory [47,48]. It is worthwhile considering that such results may be reflective of the superior baseline performance of females in cognitive measures than males or may be exacerbated by disease process, though prior research has found that sexspecific progression to cognitive impairment cannot be fully explained by this baseline performance, nor disease duration [31].…”

Parkinson’s Disease in Women and Men: What’s the Difference?

“…demonstrated that estrogens might protect against memory impairment through the regulation of neurogenic inflammation by inhibiting NF-κB activity [111]. Analogously, the reduction of estradiol level and the expression of its receptors in hippocampus of aged female rat has been shown to contribute to the deficit of spatial memory performance in the Morris water maze test [112]. Nevertheless, a recent paper recommended to carefully consider the positive effect of estrogens on cognition, suggesting that these hormones can enhance and impair learning depending on the mem-ory system [113].…”

The Different Sensitivity of Dendritic Degeneration in Hippocampal and Cortical Neurons to Estrogen Decline in Female Aging Mice

“…It has been reported that the decline of E2 is associated with cognitive de cits in female aging rats [6]. A previous study reported that female 18-20-month-old mice and female mice in same age with long-term E2 deprivation all decreased neuronal density in both the arcuate nucleus and preoptic area [50].…”

“…Estradiol (E2) is not only synthesized in ovaries but also in nonreproductive tissues, including liver, heart, muscle, bone, and brain that is consistent with a diversity of estrogen actions [5]. It has been reported that the frontal cortical E2 level reduced in female AD patients [2], and the decline of hippocampal E2 is associated with the cognitive de cits in female aging rats [6]. As per these studies, E2 de ciency might facilitate female dementia during aging.…”