Neuron-derived estrogen is critical for astrocyte activation and neuroprotection of the ischemic brain

Yujiao Lu, Gangadhara R. Sareddy, Jing Wang, Quanguang Zhang, Fu Lei Tang, Uday P. Pratap, Rajeshwar R. Tekmal, Ratna K. Vadlamudi, Darrell W. Brann

Research output: Contribution to journalArticle

Abstract

17b-Estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but the functions of neuron-derived E2 in the ischemic brain are unclear. Here, we used a forebrain neuron-specific aromatase KO (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain and determine its roles after global cerebral ischemia. We demonstrated that ovariectomized female FBN-ARO-KO mice exhibited significantly attenuated astrocyte activation, astrocytic aromatization, and decreased hippocampal E2 levels compared with FLOX mice. Furthermore, FBN-ARO-KO mice had exacerbated neuronal damage and worse cognitive dysfunction after global cerebral ischemia. Similar results were observed in intact male mice. RNA-seq analysis revealed alterations in pathways and genes associated with astrocyte activation, neuroinflammation, and oxidative stress in FBN-ARO-KO mice. The compromised astrocyte activation in FBN-ARO-KO mice was associated with robust downregulation of the astrocyte-derived neurotrophic factors, BDNF and IGF-1, as well as the astrocytic glutamate transporter, GLT-1. Neuronal FGF2, which acts in a paracrine manner to suppress astrocyte activation, was increased in FBN-ARO-KO neurons. Interestingly, blocking FGF2 signaling by central injection of FGFR3-neutralizing antibody was able to reverse the diminishment in neuroprotective astrocyte reactivity, and attenuate neuronal damage in FBN-ARO-KO mice. Moreover, in vivo E2 replacement suppressed FGF2 signaling and rescued the compromised reactive astrogliosis and cognitive deficits. Collectively, our data provide novel genetic evidence for a beneficial role of neuron-derived E2 in astrocyte activation, neuroprotection, and cognitive preservation following ischemic injury to the brain.

Original languageEnglish (US)
Pages (from-to)7355-7374
Number of pages20
JournalJournal of Neuroscience
Volume40
Issue number38
DOIs
StatePublished - Sep 16 2020

Keywords

  • 17b-estradiol
  • Aromatase
  • Astrocyte
  • Cerebral ischemia
  • Neuroprotection
  • Stroke

ASJC Scopus subject areas

  • Neuroscience(all)

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