title: Estrogen regulation of Dkk1 and Wnt/β-Catenin signaling in neurodegenerative disease.
abstract: 17β-estradiol (E2 or estrogen) is an endogenous steroid hormone that is well known to exert neuroprotection. Along these lines, one mechanism through which E2 protects the hippocampus from cerebral ischemia is by preventing the post-ischemic elevation of Dkk1, a neurodegenerative factor that serves as an antagonist of the canonical Wnt signaling pathway, and simultaneously inducing pro-survival Wnt/β-Catenin signaling in hippocampal neurons. Intriguingly, while expression of Dkk1 is required for proper neural development, overexpression of Dkk1 is characteristic of many neurodegenerative diseases, such as stroke, Alzheimer's disease, Parkinson's disease, and temporal lobe epilepsy. In this review, we will briefly summarize the canonical Wnt signaling pathway, highlight the current literature linking alterations of Dkk1 and Wnt/β-Catenin signaling with neurological disease, and discuss E2's role in maintaining the delicate balance of Dkk1 and Wnt/β-Catenin signaling in the adult brain. Finally, we will consider the implications of long-term E2 deprivation and hormone therapy on this crucial neural pathway. This article is part of a Special Issue entitled Hormone Therapy.
authors.affiliation: Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, 1120 15th Street, CA-4004, Augusta, GA 30912, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Scott
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Brann
mesh_terms: D000818:Animals; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: C577596:DKKL1 protein, human; D004967:Estrogens; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins