Brain-derived estrogen: a critical player in maintaining cognitive health of aged female rats, possibly involving GPR30

Hu, Jiewei; Huang, Yuanyuan; Gao, Fujia; Sun, Wuxiang; Liu, Huiyu; Ma, Haoran; Yuan, Tao; Liu, Zixuan; Tang, Lei; Ma, Yuxuan; Zhang, Xin; Bai, Jing; Wang, Ruimin

doi:10.1016/j.neurobiolaging.2023.04.006

Cited by 6 publications

(4 citation statements)

References 61 publications

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“…Some studies have reported that aromatase activity in the brain of healthy elderly women is increased, with brain-derived estrogen (BDE2) being six times higher than circulating E2 [ 22 , 23 ]. Our recent study confirms that in 18-month (Mon) old female rats, E2 level in the hippocampus is significantly higher than that in the serum [ 24 ]. Conditional knockout aromatase gene in forebrain neurons leads to cognitive dysfunction in rats and mice [ 25 ].…”

Section: Introductionsupporting

confidence: 86%

Brain-Derived Estrogen Regulates Neurogenesis, Learning and Memory with Aging in Female Rats

Huang

Sun

Gao

et al. 2023

Biology

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Although 17β-estradiol (E2) can be locally synthesized in the brain, whether and how brain-derived E2 (BDE2) impacts neurogenesis with aging is largely unclear. In this study, we examined the hippocampal neural stem cells, neurogenesis, and gliogenesis of 1, 3, 6, 14, and 18-month (Mon) female rats. Female forebrain neuronal aromatase knockout (FBN-ARO-KO) rats and letrozole-treated rats were also employed. We demonstraed that (1) the number of neural stem cells declined over 14-Mon age, and the differentiation of astrocytes and microglia markedly elevated and exhibited excessive activation. KO rats showed declines in astrocyte A2 subtype and elevation in A1 subtype at 18 Mon; (2) neurogenesis sharply dropped from 1-Mon age; (3) KO suppressed dentate gyrus (DG) neurogenesis at 1, 6 and 18 Mon. Additionally, KO and letrozole treatment led to declined neurogenesis at 1-Mon age, compared to age-matched WT controls; (4) FBN-ARO-KO inhibited CREB-BDNF activation, and decreased protein levels of neurofilament, spinophilin and PSD95. Notably, hippocampal-dependent spatial learning and memory was impaired in juvenile (1 Mon) and adulthood (6 Mon) KO rats. Taken together, we demonstrated that BDE2 plays a pivotal role for hippocampal neurogenesis, as well as learning and memory during female aging, especially in juvenile and middle age.

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Section: Introductionsupporting

confidence: 86%

Brain-Derived Estrogen Regulates Neurogenesis, Learning and Memory with Aging in Female Rats

Huang

Sun

Gao

et al. 2023

Biology

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“…ER1 and ER2 are essentially nuclear estrogen receptors that after activation by estrogen bind transcription factors and regulate transcription of a variety of genes involved in different cellular processes. Besides the genomic effect that occurs in the time frame of hours to days, estrogen has an instant non-genomic effect that starts in the cells within minutes of estrogen exposure, contributes to estrogen-induced neuroprotection 46 and cognitive function 47 , and is mediated by estrogen surface receptors including GPER1 48 . In fact, prior experimental studies reported that activation of GPER1 by estrogen has cell-type specific consequences as it promotes cell survival in neurons and causes apoptosis in astrocytes 49 .…”

Section: Discussionmentioning

confidence: 99%

G-protein coupled estrogen receptor 1, amyloid-β, and tau tangles in older adults

Oveisgharan,

Yu,

de Paiva Lopes

et al. 2024

Commun Biol

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Accumulation of amyloid-β (Aβ) and tau tangles are hallmarks of Alzheimer’s disease. Aβ is extracellular while tau tangles are typically intracellular, and it is unknown how these two proteinopathies are connected. Here, we use data of 1206 elders and test that RNA expression levels of GPER1, a transmembrane protein, modify the association of Aβ with tau tangles. GPER1 RNA expression is related to more tau tangles (p = 0.001). Moreover, GPER1 expression modifies the association of immunohistochemistry-derived Aβ load with tau tangles (p = 0.044). Similarly, GPER1 expression modifies the association between Aβ proteoforms and tau tangles: total Aβ protein (p = 0.030) and Aβ38 peptide (p = 0.002). Using single nuclei RNA-seq indicates that GPER1 RNA expression in astrocytes modifies the relation of Aβ load with tau tangles (p = 0.002), but not GPER1 in excitatory neurons or endothelial cells. We conclude that GPER1 may be a link between Aβ and tau tangles driven mainly by astrocytic GPER1 expression.

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“…Although gonadal synthesis progressively declines with aging, recent research suggests that the brains of female rats may adeptly compensate for this decline [ 39 ], thereby preserving protective effects also during senescence. However, it cannot be excluded that EE induces a higher level of stress in male rats per se [ 40 ]. The instinct to define the hierarchy and the inevitable confrontations that this entails may have certainly made the management of the experimental setting more challenging for males compared to females.…”

Section: Discussionmentioning

confidence: 99%

The effect of late-life environmental enrichment on stress and anxiety: The role of sex and age-related differences in coping with aversive stimuli

Balietti,

Principi,

Giacomini

et al. 2024

Heliyon

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Brain-derived estrogen: a critical player in maintaining cognitive health of aged female rats, possibly involving GPR30

Cited by 6 publications

References 61 publications

Brain-Derived Estrogen Regulates Neurogenesis, Learning and Memory with Aging in Female Rats

Brain-Derived Estrogen Regulates Neurogenesis, Learning and Memory with Aging in Female Rats

G-protein coupled estrogen receptor 1, amyloid-β, and tau tangles in older adults

The effect of late-life environmental enrichment on stress and anxiety: The role of sex and age-related differences in coping with aversive stimuli

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