MicroRNAs in the aging female brain: a putative mechanism for age-specific estrogen effects Journal Article

Authors: Rao, Y. S.; Mott, N. N.; Wang, Y; Chung, W. C.; Pak, T. R.
Article Title: MicroRNAs in the aging female brain: a putative mechanism for age-specific estrogen effects
Abstract: Menopause is characterized by the rapid age-related decline of circulating 17beta-estradiol (E(2)) levels in women, which can sometimes result in cognitive disorders such as impaired memory and increased anxiety. Hormone therapy (HT) is a widely used treatment for the adverse effects associated with menopause; however, evidence suggests that HT administered to postmenopausal women age 65 years and over can lead to increased risks for cognitive disorders. We hypothesized that these age-related changes in E(2) action are due to posttranscriptional gene regulation by microRNAs (miRNAs). miRNAs are a class of small noncoding RNAs that regulate gene expression by binding to the 3'-untranslated region of target mRNAs and subsequently target these transcripts for degradation. In the present study, 3- and 18-month-old female rats were oophorectomized (OVX) and treated 1 week after surgery with 2.5 mug E(2) once per day for 3 days. Total RNA was isolated from the ventral and dorsal hippocampus, central amygdala, and paraventricular nucleus. Our results showed that E(2) differentially altered miRNA levels in an age- and brain region-dependent manner. Multiple miRNA target prediction algorithms revealed putative target genes that are important for memory and stress regulation, such as BDNF, glucocorticoid receptor, and SIRT-1. Indeed, quantitative RT-PCR analyses of some of the predicted targets, such as SIRT1, showed that the mRNA expression levels were the inverse of the targeting miRNA, thereby confirming the prediction algorithms. Taken together, these data show that E(2) regulates miRNA expression in an age- and E(2)-dependent manner, which we hypothesize results in differential gene expression and consequently altered neuronal function.
Journal Title: Endocrinology
Volume: 154
Issue: 8
ISSN: 1945-7170; 0013-7227
Publisher: Unknown  
Journal Place: United States
Date Published: 2013
Start Page: 2795
End Page: 2806
Language: eng
Notes: LR: 20150604; GR: AG033605/AG/NIA NIH HHS/United States; GR: R00 HD058044/HD/NICHD NIH HHS/United States; GR: R01 AG033605/AG/NIA NIH HHS/United States; JID: 0375040; 0 (Brain-Derived Neurotrophic Factor); 0 (Estrogens); 0 (MicroRNAs); 0 (Receptors, Glucocorticoid); 4TI98Z838E (Estradiol); EC 3.5.1.- (Sirt1 protein, rat); EC 3.5.1.- (Sirtuin 1); CIN: Endocrinology. 2013 Aug;154(8):2570-2. PMID: 23873768; OID: NLM: PMC3713211; 2013/05/29 [aheadofprint]; ppublish