Gamma secretase activity modulates BMP-7-induced dendritic growth in primary rat sympathetic neurons

• Published in: Autonomic neuroscience Vol. 247; p. 103085
• Main Authors: Karunungan, Krystal, Garza, Rachel H., Grodzki, Ana Cristina, Holt, Megan, Lein, Pamela J., Chandrasekaran, Vidya
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-07-2023
• Subjects: Amyloid Precursor Protein Secretases - metabolism; Amyloid Precursor Protein Secretases - pharmacology; Animals; BMS-299897; Bone Morphogenetic Protein 7 - metabolism; Bone Morphogenetic Protein 7 - pharmacology; Bone morphogenetic proteins; Cells, Cultured; DAPT; Dendrite; Dendrites - metabolism; LY-411575; Neurons - metabolism; Presenilin; Rats; Sympathetic neurons; γ-Secretase; BMP; Sympathetic neurons; BMS-299897; LY-411575; Presenilin; NGF; γ-Secretase; Dendrite; SCG; Bone morphogenetic proteins; TGF-β; GAPDH; DAPT
• DOI: 10.1016/j.autneu.2023.103085
• EISSN: 1872-7484
• ISSN: 1566-0702; 1872-7484

Autonomic dysfunction has been observed in Alzheimer's disease (AD); however, the effects of genes involved in AD on the peripheral nervous system are not well understood. Previous studies have shown that presenilin-1 (PSEN1), the catalytic subunit of the gamma secretase (γ-secretase) complex, mutations in which are associated with familial AD function, regulates dendritic growth in hippocampal neurons. In this study, we examined whether the γ-secretase pathway also influences dendritic growth in primary sympathetic neurons. Using immunoblotting and immunocytochemistry, molecules of the γ-secretase complex, PSEN1, PSEN2, PEN2, nicastrin and APH1a, were detected in sympathetic neurons dissociated from embryonic (E20/21) rat sympathetic ganglia. Addition of bone morphogenetic protein-7 (BMP-7), which induces dendrites in these neurons, did not alter expression or localization of γ-secretase complex proteins. BMP-7-induced dendritic growth was inhibited by siRNA knockdown of PSEN1 and by three γ-secretase inhibitors, γ-secretase inhibitor IX (DAPT), LY-411575 and BMS-299897. These effects were specific to dendrites and concentration-dependent and did not alter early downstream pathways of BMP signaling. In summary, our results indicate that γ-secretase activity enhances BMP-7 induced dendritic growth in sympathetic neurons. These findings provide insight into the normal cellular role of the γ-secretase complex in sympathetic neurons.
•γ-Secretase complex members are present in the cell body and processes of sympathetic neurons.•Inhibition of γ-secretase activity decreases BMP-7-induced dendritic growth.•The inhibitors selectively inhibit dendritic growth without affecting axonal growth.•γ-Secretase inhibition does not alter SMAD nuclear translocation downstream of BMP.