Depression-like Behavior and Alterations of Neurotransmitters and the Corresponding Receptors in the Triple Transgenic Mouse Model of Alzheimer's Disease

Abstract

Abstract Backgrounds: Depression is among the most frequent psychiatric comorbid conditions in Alzheimer’s disease (AD). However, pharmacotherapy for depressive disorders in AD is still a big challenge；current antidepressants used clinically, such as monoamine antidepressants, have shown only modest or little clinical benefits. Here we investigated the mechanism of the interactions between depression and AD, which we believe would aid in the development of pharmacological therapeutics for the comorbidity of depression and AD. Methods: Female APP/PS1/Tau triple transgenic (3×Tg-AD) mice at 20 months of age and age- and gender-matched wild-type (WT) mice were used. The shuttle-box passive avoidance test (PAT), the open field test (OFT), and the tail suspension test (TST) were implemented to assess behavioral changes. High-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used to detect the level of neurotransmitters related to depression in the hippocampus of mice. The data was identified by orthogonal projections to latent structures discriminant analysis (OPLS-DA). The expression of relative receptors was detected using Western blot. Results: Compared to WT, 3×Tg-AD mice displayed significant cognitive impairment in the PAT and depression-like behavior in the OFT and TST. They also showed significant decreases in the levels of L-tyrosine, norepinephrine, vanillylmandelic acid, 5-hydroxytryptamine, and acetylcholine, in contrast to significant increases in 5-hydroxyindoleacetic acid, L-histidine, L-glutamine, and L-arginine in the hippocampus. The expression of the alpha 1a adrenergic receptor (ADRA1A), serotonin 1A receptor (5HT1A), and γ-aminobutyric acid A receptor subunit alpha-2 (GABRA2) was significantly downregulated in the hippocampus of 3×Tg-AD mice, while histamine H3 receptor (H3R) expression was significantly upregulated. In addition, the ratio of phosphorylated cAMP-response element-binding protein (pCREB) and CREB was significantly decreased in the hippocampus relative to WT. Conclusions: We demonstrated in the present study that aged female 3×Tg-AD mice showed depression-like behavior accompanied with cognitive dysfunction. The complex and diverse mechanism appears not only relevant to the imbalance of multiple neurotransmitter pathways, including the transmitters and receptors of the monoaminergic, GABAergic, histaminergic, and cholinergic systems, but also related to the changes in L-arginine and CREB signaling molecules.