Age-dependent alterations of TRPA1 and urocortin 1 signaling in the Edinger-Westphal nucleus in a mouse model of Alzheimer's disease.

Abstract

Cholinergic neurons of the preganglionic Edinger-Westphal nucleus (EW) are involved in Alzheimer's disease (AD), however, the role of urocortin 1 (UCN1) positive peptidergic neurons of the centrally projecting EW (EWcp) remains unclear. EWcp cells exclusively express transient receptor potential ankyrin 1 (TRPA1) ion channels, implicated in neurodegenerative disorders. We hypothesized that the EWcp/UCN1/Trpa1 neurons may be involved in AD-related pathologies. Age-dependent (2, 6, 9, 12 and 18 months) Trpa1 mRNA expression (RNAscope in situ hybridization) and UCN1 peptide (immunostaining) content of the EWcp were examined in male triple transgenic mouse (3xTg-AD) model of AD.H-MRI spectroscopy was performed in the hippocampus at 6, 12 and 18 months to evaluate the taurine and N-acetylaspartate levels, metabolites reflecting neuroprotection and neuronal integrity as AD prognostic markers. Trpa1 expression was lower in 2 and 6-months-old 3xTg-AD than controls. Later the genotype differences disappeared due to the progressive, age-related reduction of Trpa1 mRNA transcripts in the controls. In contrast, the Trpa1 expression of transgenic mice remained persistently low. Similarly, the UCN1 peptide content was also lower in the 2 and 6-months-old 3xTg-AD compared to controls. However, UCN1 level increased with age, which was more pronounced in 3xTg-AD than controls abolishing the genotype differences. Age-dependent decrease in taurine level was detected in transgenic animals leading to significantly lower taurine/creatine ratio in 12 and 18-months-old 3xTg-AD animals compared to the controls. This age-related dynamics of Trpa1 and UCN1 expression of 3xTg-AD mice suggests that altered UCN1 signaling may contribute to AD-associated mood disorders and memory decline.