Concomitant expression of BACE1 and the p75 neurotrophin receptor after injury
Khalil Saadipour1, Wilma J. Friedman2, Paul M. Mathews3, Helen E. Scharfman3, Moses V. Chao1
1Department of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, New York, NY 10016, USA; 2Department of Biological Sciences, Rutgers Life Sciences Center, Rutgers University, Newark, NJ 07102, USA; 3Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA
Following injury, cellular stress, and seizures, the p75 neurotrophin receptor, p75NTR, levels are dramatically increased in the central nervous system. Similar to p75NTR, the expression of beta-site APP cleaving enzyme 1, BACE1, in neurons is also enhanced in response to stress and after traumatic brain injury. Both proteins are implicated in neurodegenerative processes, and BACE1 is directly involved in the pathogenesis of Alzheimer's disease. Here, we investigated whether the expression of p75NTR has an effect upon BACE1 expression levels.
Our results showed that the levels of p75NTR and BACE1 are increased concomitantly in the 3-month old mouse brain cortex 72 hours following experimental traumatic brain injury. Moreover, the level of endogenous BACE1 in p75NTR wild type mouse cortical neurons (P1) is significantly higher than in neurons from the p75NTR (exon III) knock out. To examine whether a direct link exists between p75NTR and BACE1, transfection experiments of p75NTR was carried out in SH-SY5Y cells. Overexpression of p75NTR led to an increase of BACE1 expression. Other studies indicated that BACE1 expression is sensitive to the c-Jun N-terminal kinase (JNK) activity. p75NTR is known to activate JNK. We found that treatment with a JNK inhibitor, SP600125, significantly prevented the up-regulation of BACE1 following p75NTR transfection.
Taken together, these experiments indicate a link between p75NTR signaling and BACE1 expression and suggest both proteins are under similar regulatory control after nerve injury that has consequences in neurodegenerative diseases.
Keyword: p75 neurotrophin receptor, BACE1, JNK, injury, Alzheimer's disease