| Gonadotropin-releasing hormone receptor (GnRHR1) signaling promotes gonadotropin synthesis and secretion from pituitary gonadotrophs. GnRHR1 signaling in healthy or degenerating neurons has not been well-characterized. To investigate GnRHR1 signaling in the brain, I examined the following: (1) GnRHR1 localization in human brain tissue/neurons and their functionality, (2) amyloid-beta precursor protein (AbetaPP) processing and neurosteroid production as downstream effectors of GnRHR1 signaling, and (3) the influence of GnRH1 and GnRHR1 polymorphisms on Alzheimer's disease (AD). GnRHR1 is localized to pyramidal and neocortical neurons of the human brain as well as M17 neuroblastoma cells and primary rat cortical neurons. Neuronal GnRHR1 is functional as evidenced by the modulation of phosphorylation of protein kinase C and expression of luteinizing hormone (LH) in the presence of GnRH1 and the GnRH1 antagonist antide. GnRHR1 in neuroblastoma cells does not signal via the MAPK pathway. GnRH1 did not alter AbetaPP expression or processing, although changes were observed in secreted amyloid-beta (Abeta) levels, the major component of amyloid plaques in the AD brain. GnRH1 treatment of M17 neuroblastoma cells did not alter the secreted levels of progesterone. Finally, a novel polymorphism was found in the promoter region of the GnRH1 gene and together with APOE was found to be significant for predicting AD in 2 of 3 genetic tests used; linkage disequilibrium (LD) and multifactor dimensionality reduction (MDR). A gene-gene interaction between a GnRH exon 1 and LH receptor 1 polymorphism was found to have an odds ratio of 5.72 (1.01, 32.23; p<0.048), suggesting a nearly 5-fold increase in susceptibility to late-onset AD. This interaction was also observed in the LD analyses for the AD female cohort. Taken together, our results indicate the presence of functional GnRH receptors in human neurons, which may modulate LH expression and AbetaPP metabolism. Mutations in GnRH1 and/or GnRHR1 may regulate signaling via this receptor and the pathogenesis of AD. |
