ABSTRACT
BACKGROUND/AIMS: Calcium homeostasis plays a crucial role in neuronal development and disease. Calbindin-D9k (CaBP-9k) acts as calcium modulators and sensors in various tissues. However, the neurobiological functions of CaBP-9k are unknown. METHODS: We used CaBP-9k knockout (KO) mice to investigate the roles of these gene in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We used anatomical and biochemical approaches to characterize functional abnormalities of the brain in the CaBP-9k KO mice. RESULTS: We found that the brains of CaBP-9k KO mice have increased APP/ß-amyloid, Tau, and α-synuclein accumulation and endoplasmic reticulum (ER) stress-induced apoptosis. Neurons deficient for these CaBP-9k had abnormal intracellular calcium levels and responses. ER stress inhibitor TUDCA reduced ER stress-induced apoptosis and restored ER stress- and apoptosis-related proteins expression to wild-type levels in CaBP-9k KO mice. Furthermore, treatment with TUDCA rescued the abnormal memory and motor behaviors exhibited by older CaBP-9k KO mice. CONCLUSION: Our results suggest that a loss of CaBP-9k may contribute to the onset and progression of neurodegenerative diseases.
Subject(s)
Alzheimer Disease/genetics , Apoptosis/genetics , Calbindins/genetics , Endoplasmic Reticulum Stress/genetics , Parkinson Disease/genetics , Taurochenodeoxycholic Acid/therapeutic use , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Apoptosis/drug effects , Brain/metabolism , Brain/pathology , Calbindins/metabolism , Calcium/metabolism , Cell Proliferation/genetics , Cells, Cultured , Endoplasmic Reticulum Stress/drug effects , Maze Learning/drug effects , Memory Disorders/drug therapy , Memory Disorders/genetics , Mice , Mice, Knockout , Motor Activity/drug effects , Motor Activity/genetics , Neurons/metabolism , Neurons/pathology , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , RNA, Small Interfering , Risk Factors , Taurochenodeoxycholic Acid/pharmacology , alpha-Synuclein/metabolism , tau Proteins/metabolismABSTRACT
This study investigated the effect of dexamethasone (DEX) on intracellular calcium levels and the expressions of transient receptor potential cation channel subcomponent V member 6 (TRPV6), sodium-calcium exchanger 1 (NCX1), and plasma membrane calcium ATPase 1 (PMCA1) in A549 cells. The intracellular calcium level, by using the calcium indicator pGP-CMV-GCaMP6f, increased following DEX treatment for 6, 12, and 24 h in A549 cells. In addition, Rhod-4 assay after DEX treatment for 24 h showed that DEX increased the level of intracellular calcium. The expression of the calcium influx TRPV6 gene significantly increased, whereas the expressions of the calcium outflow NCX1 and PMCA1 genes significantly decreased with DEX treatment. The mRNA levels of surfactant protein genes SFTPA1, SFTPB, SFTPC, and SFTPD and the secreted airway mucin genes MUC1 and MUC5AC were investigated by treating cells with DEX. The DEX treatment decreased the mRNA levels of SFTPA1 and SFTPB but increased the mRNA levels of SFTPC and SFTPD. The MUC1 mRNA level was increased by DEX treatment, whereas MUC5AC mRNA was significantly decreased. These results indicate that DEX influences the intracellular calcium level through TRPV6, and affects pulmonary surfactant genes and secreted airway mucin genes in A549 cells.
