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.