Regulation of BACE1 expression after injury is linked to the p75 neurotrophin receptor

Khalil Saadipour, Alexia Tiberi, Sylvia Lomardo, Elena Grajales, Laura Montroull, Noralyn B. Mañucat-Tan, John LaFrancois, Michael Cammer, Paul M. Mathews, Helen E. Scharfman, Francesca Fang Liao, Wilma J. Friedman, Xin Fu Zhou, Giueseppina Tesco, Moses V. Chao

Research output: Contribution to journalArticle

Abstract

BACE1 is a transmembrane aspartic protease that cleaves various substrates and it is required for normal brain function. BACE1 expression is high during early development, but it is reduced in adulthood. Under conditions of stress and injury, BACE1 levels are increased; however, the underlying mechanisms that drive BACE1 elevation are not well understood. One mechanism associated with brain injury is the activation of injurious p75 neurotrophin receptor (p75), which can trigger pathological signals. Here we report that within 72 h after controlled cortical impact (CCI) or laser injury, BACE1 and p75 are increased and tightly co-expressed in cortical neurons of mouse brain. Additionally, BACE1 is not up-regulated in p75 null mice in response to focal cortical injury, while p75 over-expression results in BACE1 augmentation in HEK-293 and SY5Y cell lines. A luciferase assay conducted in SY5Y cell line revealed that BACE1 expression is regulated at the transcriptional level in response to p75 transfection. Interestingly, this effect does not appear to be dependent upon p75 ligands including mature and pro-neurotrophins. In addition, BACE1 activity on amyloid precursor protein (APP) is enhanced in SY5Y-APP cells transfected with a p75 construct. Lastly, we found that the activation of c-jun n-terminal kinase (JNK) by p75 contributes to BACE1 up-regulation. This study explores how two injury-induced molecules are intimately connected and suggests a potential link between p75 signaling and the expression of BACE1 after brain injury.

Original languageEnglish
Article number103395
Number of pages15
JournalMolecular and Cellular Neuroscience
Volume99
DOIs
Publication statusPublished - Sep 2019
Externally publishedYes

Keywords

  • BACE1
  • JNK
  • p75 neurotrophin receptor
  • Traumatic brain injury

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    Saadipour, K., Tiberi, A., Lomardo, S., Grajales, E., Montroull, L., Mañucat-Tan, N. B., LaFrancois, J., Cammer, M., Mathews, P. M., Scharfman, H. E., Liao, F. F., Friedman, W. J., Zhou, X. F., Tesco, G., & Chao, M. V. (2019). Regulation of BACE1 expression after injury is linked to the p75 neurotrophin receptor. Molecular and Cellular Neuroscience, 99, [103395]. https://doi.org/10.1016/j.mcn.2019.103395