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

被引:7
|
作者
Saadipour, Khalil [1 ,2 ,3 ]
Tiberi, Alexia [1 ,2 ,3 ,4 ]
Lomardo, Sylvia [5 ]
Grajales, Elena [1 ,2 ,3 ]
Montroull, Laura [6 ]
Manucat-Tan, Noralyn B. [7 ]
LaFrancois, John [8 ]
Cammer, Michael [9 ]
Mathews, Paul M. [8 ]
Scharfman, Helen E. [8 ]
Liao, Francesca-Fang [10 ]
Friedman, Wilma J. [6 ]
Zhou, Xin-Fu [7 ]
Tesco, Giueseppina [5 ]
Chao, Moses, V [1 ,2 ,3 ]
机构
[1] NYU, Langone Med Ctr, Skirball Inst Biomol Med, Dept Cell Biol, New York, NY 10016 USA
[2] NYU, Langone Med Ctr, Skirball Inst Biomol Med, Dept Physiol & Neurosci, New York, NY 10016 USA
[3] NYU, Langone Med Ctr, Skirball Inst Biomol Med, Dept Psychiat, New York, NY 10016 USA
[4] Scuola Normale Super Pisa, Bio SNS Lab, Piazza Cavalieri 7, I-56126 Pisa, Italy
[5] Tufts Univ, Alzheimers Dis Res Lab, Sch Med, 136 Harrison Ave, Boston, MA 02111 USA
[6] Rutgers State Univ, Rutgers Life Sci Ctr, Dept Biol Sci, Newark, NJ 07102 USA
[7] Univ South Australia, Sch Pharm & Med Sci, Sansom Inst, Adelaide, SA 5000, Australia
[8] Ctr Dementia Res, Nathan Kline Inst Psychiat Res, Orangeburg, NY 10962 USA
[9] NYU, Langone Med Ctr, DART Microscopy Lab, New York, NY 10016 USA
[10] Univ Tennessee, Dept Pharmacol, Hlth Sci Ctr, Memphis, TN 38163 USA
基金
美国国家卫生研究院;
关键词
BACE1; p75 neurotrophin receptor; JNK; Traumatic brain injury; AMYLOID PRECURSOR PROTEIN; TRAUMATIC BRAIN-INJURY; GROWTH-FACTOR RECEPTOR; NF-KAPPA-B; BETA-SECRETASE BACE1; ALZHEIMERS-DISEASE; MESSENGER-RNA; NERVE; NEURONS; ACTIVATION;
D O I
10.1016/j.mcn.2019.103395
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
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页数:15
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