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. Author manuscript; available in PMC: 2020 Sep 1.
Published in final edited form as: Mol Cell Neurosci. 2019 Aug 15;99:103395. doi: 10.1016/j.mcn.2019.103395

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

Khalil Saadipour 1, Alexia Tiberi 1,2, Sylvia Lomardo 3, Elena Grajales 1, Laura Montroull 4, Noralyn B Mañucat-Tan 5, John LaFrancois 6, Michael Cammer 7, Paul M Mathews 6, Helen E Scharfman 6, Francesca-Fang Liao 8, Wilma J Friedman 4, Xin-Fu Zhou 5, Giueseppina Tesco 3, Moses V Chao 1
PMCID: PMC6993608  NIHMSID: NIHMS1546592  PMID: 31422108

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 hours 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.

Keywords: BACE1, p75 neurotrophin receptor, JNK, traumatic brain injury

Introduction

BACE1, the β-site amyloid precursor protein cleaving enzyme-1, is a transmembrane aspartyl protease, which is highly expressed in the brain during early development but decreases in adulthood (Laird et al., 2005; Sinha et al., 1999; Vassar et al., 1999; Willem et al., 2006). BACE1 is a multi-functional enzyme that cleaves many cellular substrates such as Jagged1, CHL1, Nrgl1, VEGFr1, and NaVβ2, which are crucial for normal brain function. A large number of substrates suggests that BACE1 plays critical roles in the homeostasis of the brain, and thus it must be precisely regulated. For instance, the deletion of BACE1 in mice leads to complex deleterious neurological phenotypes such as hypomyelination, hyperactivity, memory deficits, seizures, growth retardation, and schizophrenia (Gersbacher et al., 2010; Hu et al., 2008; Hu et al., 2013; Kim et al., 2007; Rajapaksha et al., 2011; Savonenko et al., 2008; Zhou et al., 2012). BACE1 is a well-established initiator of the amyloidogenic cleavage of amyloid precursor protein (APP), resulting in Aβ peptide generation that contributes to Alzheimer’s disease (AD) pathogenesis (Hardy and Higgins, 1992; Selkoe, 1991; Vassar et al., 1999).

BACE1 levels are increased in response to a wide variety of pathological conditions including ischemia, oxidative stress, neurodegenerative diseases, as well as traumatic brain injury (TBI) (Blasko et al., 2004; Fukumoto et al., 2002; Tamagno et al., 2002; Tong et al., 2005; Walker et al., 2012; Wen et al., 2004; Yang et al., 2003). Although inflammation and injury dependent regulatory pathways such as NF-κB and c-jun n-terminal kinase (JNK) are reported to positively regulate BACE1 expression (Guglielmotto et al., 2011; Wang et al., 2015), the exact underlying mechanisms by which these pathways are activated are uncertain.

The p75 neurotrophin receptor is a transmembrane protein that belongs to the tumor necrosis factor (TNF) receptor superfamily. It has an extracellular domain (ECD) with cysteine-rich repeats and an intracellular region (ICD) containing a death domain (Liepinsh et al., 1997; Lin et al., 2015). The negative charge of the ECD allows the receptor to bind to positively charged mature and pro-neurotrophins (Vilar et al., 2009). p75 recruits both pro-survival and pro-apoptotic signaling, but these actions depend on its expression levels, the type of cells it is expressed in, the type of ligands bind to p75, and the co-receptor it interacts with (Irmady et al., 2014; Lu et al., 2005).

p75, like BACE1, is widely expressed in the developing nervous system and its levels are subsequently decreased during adulthood (Kohn et al., 1999; Singh and Miller, 2005; Willem et al., 2006). p75 is up-regulated under several pathological and inflammatory conditions and contributes to cell death (Ibanez and Simi, 2012; Lee et al., 2001; Roux et al., 1999; VonDran et al., 2014). Many types of injury and cellular stressors potentially stimulate p75 expression in the nervous system in various cell types. For instance, peripheral nerve crush and transection promotes p75 expression in glial cells and sensory neurons (Koliatsos et al., 1991; Saika et al., 1991). p75 is found to be enhanced in Schwann cells in distal sciatic nerve segments after axotomy and demyelinating lesions (Petratos et al., 2003). Ischemic injury is reported to augment p75 expression in the brain (Dmitrieva et al., 2016; Kokaia et al., 1998). p75 is highly increased in the hippocampus and cortex following seizures (Roux et al., 1999; VonDran et al., 2014) and its levels are elevated after TBI in the cortex (Alder et al., 2016; Delbary-Gossart et al., 2016; Ibanez and Simi, 2012). Because BACE1 and p75 possess similar, unique expression patterns in the brain under pathological conditions and have a suggested interaction (Saadipour et al., 2018a), we sought to investigate if p75 is associated with the regulation of BACE1 expression after brain injury.

Experimental procedure

Antibodies and reagents

Goat polyclonal anti- p75 (Cat. No. AF1157, R&D Systems, Minneapolis, MN, USA), rabbit ranti-p75ICD (9991) (Zampieri et al., 2005), anti-p75ECD antiserum (9651) (Huber and Chao, 1995), rabbit anti-Fas receptor (M20, Cat. No. sc-716, Santa Cruz, Dallas, TX, USA), rabbit monoclonal anti- BACE1 (D10E5, Cat. No. 5606, Cell Signaling Technology, Danvers, MA, USA), rabbit SAPK/JNK (Cat No. 9252, Cell Signaling Technology), rabbit phospho-SAPK/JNK (Thr183/Tyr185) (Cat No. 9251, Cell Signaling Technology), mouse anti-glial fibrillary acidic protein (GFAP) (Cat. No. 556330, Biosciences, Bedford, MA, USA), chicken anti-NeuN (Cat No. ABN91, Millipore, Burlington, MA, USA), mouse anti-APP (22C11, Cat. No. MAB384) (Millipore, Burlington, MA, USA), anti-APP (C1/6.1 and m3.2) antibodies (Choi et al., 2009), and mouse monoclonal anti- β- actin (AC-74, Cat. No. A2228, Sigma- Aldrich, St Louis, MO, USA) were used as primary antibodies in the present study. All HRP- linked and fluorescence secondary antibodies were obtained from Sigma- Aldrich (St Louis, MO, USA) and Invitrogen (Carlsbad, CA, USA), respectively. NGF (Cat. No. 45034) and BDNF (Cat. No. 45002) recombinant proteins were obtained from PeproTech (Rocky Hill, NJ, USA). Recombinant proNGF was kindly provided by Dr. Barbara L. Hempstead (Weill Cornell School of Medicine, New York, NY).

Animals

p75 knockout (p75 ExonIII−/− or p75−/−) and p75 wild type (B6.SJL or p75+/+) mice were obtained from the Jackson Laboratory and Francis S. Lee lab (Weill Cornell School of Medicine, New York, NY) (Lee et al., 1992). Their genotype was determined by PCR analyses of tail DNA (Bentley and Lee, 2000). Animals were maintained under standard conditions at 22°C, with a 12 hours light/dark cycle and food/water ad libitum. All procedures were approved under New York University Institutional Animal Care and Use Committees in accordance with US National Institutes of Health guidelines.

Primary neuron and cell lines culture and transfections

Primary cortical neurons were isolated from E18 p75−/−and p75+/+ mice, cultured on Poly-D-Lysine coated coverslips or 6-well plates, and maintained for 3 days in vitro (DIV-III) in Neurobasal medium containing B27 supplement, 0.5 nM L-glutamine. Human neuroblastoma (SY5Y) and human embryonic kidney 293 (HEK-293) cells were obtained from American Type Culture Collection (Manassas, VA, USA). Human neuroblastoma cell line stably expressing human APP695 isoform (SY5Y- APP695) was provided by Dr. Elizabeth Eckman (Biomedical Research Institute of New Jersey, NJ, USA) (Pacheco-Quinto and Eckman, 2013). The cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM) (Invitrogen, Carlsbad, CA, USA) containing 10% fetal bovine serum (FBS) supplemented with 100 U/ml penicillin, 100 mg/ml streptomycin, 2 mM glutamine, and 200 mg/ml G418 (Invitrogen, Carlsbad, CA, USA). The plasmid transfection was performed using Lipofectamine 2000™ (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s instructions.

Controlled cortical impact (CCI) injury

B6.SJL male mice at the age of P90 were anesthetized with isoflurane in O2 using a vaporizer, positioned in a stereotaxic frame (David Kopf Instruments, LA, CA, USA). The body temperature was maintained at 37°C using a computer-controlled infrared heating pad (Kent Scientific, Torrington, CT, USA). Following a mid-line incision, a 5 mm craniotomy was conducted using a portable drill over the left somatosensory cortex. The bone flap was removed ensuring no damage to the underlying dura. Mice were then subjected to a controlled cortical impact (CCI) using a pneumatic impactor with a 3 mm flat tip at speed of 4 m/s, depth 1.5 mm, and with a dwell time of 150 msec. Cotton swabs were used to stop bleeding and the scalp was sutured afterward. Mice were allowed to recover in their cage before being placed back in the animal facility. Similar to the CCI group, sham animals also received anesthesia, incision and craniotomy over the left somatosensory cortex. The bone flap was removed, but they were not subjected to CCI. All animals received 3% body weight of 0.9% saline subcutaneously to prevent dehydration (Walker et al., 2012). All procedures were approved by Tufts University Institutional Animal Care and Use Committees, in accordance with US National Institutes of Health guidelines. After 24, 48, 72, and 96 hours of the CCI experiment, mice were anesthetized with isoflurane and perfused transcardially with cold PBS followed by 4% paraformaldehyde (PFA). The brain was post-fixed overnight in 4% PFA, and then transferred into 30% sucrose solution until 48 hours. The brain tissue was then subjected to free-floating coronal sectioning at 40 μm using a Cryostat (Leica CM3050-S).

Two-photon laser injury in the cortex

A highly localized injury was performed by focusing a two-photon laser beam (~1 μm in size) in the superficial layers of the motor cortex (M1) (~50 μm from the pia mater) through a cranial window. Both p75−/− and p75+/+ male mice (P90) were anesthetized intraperitoneally with Ketamine (200 mg/kg body weight) and Xylazine (30 mg/kg body weight) in 0.9% NaCl solution. A region (~1 mm in diameter) over the motor cortex was first thinned with a high-speed drill under a dissecting microscope and then scraped with a microsurgical blade to a final thickness of ~20 μm. The motor cortex (~1–2mm in diameter) was opened with a needle. A drop (~200 μl) of artificial mouse cerebrospinal fluid (ACSF) was applied on the exposed region for the duration of the experiment. The skull surrounding the open window was attached to a custom-made steel plate to reduce respiratory-induced movement. The animal was placed under a custom-made two-photon microscope. The wavelength of the two-photon laser was set at 780 nm and the laser power was measured to be 60–80 mW. The beam was turned on for approximately 1–3 s to create a small injury site as indicated by a bright autofluorescent sphere (~15 μm in diameter) around the focal point of the beam. The animal was then sutured and left to recover. A non-lesioned control area was considered to be 200 μm away from the original lesion site. In addition, the contralateral side was subjected to the same procedure, without the laser lesion as a control. After 72 hours post injury the animal was perfused with PBS, followed by a perfusion with 4% PFA. After overnight post-fixation, the brain was cut to 100 μm thick slices using a vibratome (Leica VT1000S) and processed for immunostaining (Davalos et al., 2005; Grutzendler et al., 2002).

Immunostaining assay

Both brain sections and primary cortical neurons were blocked in 2.5% donkey serum containing 0.1% Triton- X 100 in PBS for 1 hour at room temperature (21°C), then incubated with primary antibodies in 1% donkey serum/PBS/Triton at 4°C overnight, followed by incubation with secondary florescence antibodies in 1% donkey serum/PBS/Triton for 2 hours at room temperature (21°C). The brain sections and cells were incubated with DAPI for 15 min to stain nuclei and they were mounted using VECTASHIELD antifade mounting medium (John Morris Scientific Pty Ltd, CA, USA) on the slides. The fluorescent signals were captured and quantified by Zeiss LSM-800 confocal microscopy (New York University School of Medicine) and Fiji software, respectively. For CCI immunostaining, the number of NeuN (+) or GFAP (+) cells expressing both p75 and BACE1 within 300 μm diamater from the injury site was calculated and divided to the total number of NeuN and GFAP cells. The data was normalized between 0 to 100 and reported as as percentage. For laser injury immunostaining, the fluorescence intensity of BACE1 and p75 in p75−/− and p75+/+ mice was measured within 200 μm diamater from focal injury site. In p75−/− and p75+/+ primary neurons, the BACE1 flouresence intensity was measured.

Quantitative Real-time RT-PCR

The total RNAs were extracted from SY5Y cells transfected with 1 μg p75 or mock plasmid using RNeasy mini kit (Qiagen, Hilden, Germany). RNA was then converted to cDNA using iScrip™ cDNA synthesis kit (Bio-Rad Hercules, CA, USA). The expression levels of BACE1 and p75 were measured using Applied biosystems real-time PCR system and SYBR™ green master mix (Invitrogen, Carlsbad, CA, USA). The following primers: human BACE1 (forward 5’- TTTCCCAGTCATCTCACTCTAC-3’ and reverse 5’-CAGCAAAGCAATTCGTTTTCG-3’), rat p75 (forward 5’- TCCAGAGCAAGACCTTGTAC-3’ and reverse 5’-AGCAATATAGGCCACAAGGC-3’), and human GAPDH (forward 5’-AGGGCTGCTTTTAACTCTGGT-3’ and reverse 5’- CCCCACTTGATTTTGGAGGGA-3’) were obtained from Eurofins-Genomics (Louisville, KY, USA). The relative expression of genes was calculated using the comparative Ct (2−ΔΔCT) method. GAPDH served as an endogenous loading control.

Luciferase assay

SY5Y cells were co-transfected with rat full length/mutant BACE1 promoter and rat p75 constructs (Wang et al., 2015; Wang et al., 2013). A mock vector and the Fas receptor cDNA were used as a control for p75. The promoter activity was measured by the luciferase assay (Promega, Madison, WI, USA). The luciferase signal was detected by PerkinElmer EnSpire plate reader 2300 (Waltham, Massachusetts, USA).

Western blot

Primary neurons or cells were lysed in radioimmunoprecipitation assay (RIPA) buffer containing 50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM EDTA, 0.5% Sodium deoxycholate, 0.1% SDS, and 1% Triton X-100 supplemented with protease inhibitor cocktail (Sigma-Aldrich, St Louis, MO, USA). Total protein (30 μg) was separated by SDS page gel electrophoresis and transferred to 0.2 μm nitrocellulose membrane (GE Healthcare, Uppsala, CA, USA). The membrane was blocked with 3% bovine serum albumin (BSA) in Tris-buffered saline with tween 20 (TBST) for 1 hour at room temperature and then incubated with primary antibodies in 3% BSA/TBST at 4°C for overnight, followed by incubation with HRP-linked secondary antibodies in 3% BSA/TBST for 1 hour at room temperature. The membrane was developed using either Image Quant LAS 4000 (GE Healthcare) or Chemidoc M (Bio-rad, Hercules, CA, USA). Fiji software was used for quantitative analysis.

Statistical analysis

All statistical analyses were performed using GraphPad Prism-6 provided by New York University School of Medicine. Variables between groups were determined by either One-way repeated measures analysis of variance (ANOVA) or Student’s t-test. Values of p<0.05 were considered statistically significant. Data is presented as mean±SEM.

Results

BACE1 is highly expressed in the brain in early development but not during adulthood

BACE1 is highly expressed in the brain during prenatal and neonatal stages, after which it gradually declines to lower levels in adulthood (Willem et al., 2006). To confirm this expression pattern, we measured BACE1 in mouse brain using two time points, E18 (early development) and P90 (adult), by an immunohistochemistry (IHC) assay with a specific BACE1 (D10E5) antibody (He et al., 2005; Hitt et al., 2012). High levels of BACE1 were found in E18 brain. However, in P90 brain, BACE1 was detected at low levels except in the dentate gyrus mossy fibers, where there was high BACE1 concentrations, (Figure-1) which is consistent with previous reports (Hitt et al., 2012; Kandalepas et al., 2013; Zhao et al., 2007).

Figure-1: BACE1 expression patterns in the E18 and P90 mouse brains.

Figure-1:

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Coronal sections from the right brain hemisphere of E18 and P90 B6.SJL mice were stained for BACE1 expression (green) using anti-BACE1 (D10E5, Cell signaling) antibody. DAPI (blue) is utilized to stain nuclei. “Merge” is the combination of DAPI and BACE1. n=4 mice, CTX: cortex, CA: cornu ammonis, DG: dentate gyrus, scale bar: 200 μm.

Concomitant expression of BACE1 with p75 in the mouse brain cortex following CCI

To investigate the underlying mechanisms of BACE1 elevation after injury, CCI, a reproducible and reliable experimental TBI model using a pneumatic impactor, was applied on the somatosensory in the adult mice brain (Figure-2a,b). TBI is highly associated with pronounced disabilities and motor problems that are accompanied by vast alterations in gene expression (Lipponen et al., 2016). It is also associated with cognitive impairments similar to those that are observed in AD (Roberts et al., 1994; Uryu et al., 2007). Indeed, BACE1 in directly involved in the pathogenesis of AD by initiating β- site cleavage of APP (Hardy and Higgins, 1992; Selkoe, 1991; Vassar et al., 1999). Unexpectedly, BACE1 along with p75 neurotrophin receptor, a TNF superfamily member (Chao et al., 1986), are elevated and highly co-expressed 72 hours after injury within 300 μm from the injury site. However, neither p75 nor BACE1 could be detected in the sham cortex, undergoing a similar surgical procedure to the CCI group without receiving the impact (Figure-2c). BACE1 and p75 levels were also measured at 24, 48, 72, and 96 hours after injury by IHC, with the highest levels of BACE1 and p75 were found at 72 hours post-injury (Table-1) (Alder et al., 2016; Blasko et al., 2004; Delbary-Gossart et al., 2016; Walker et al., 2012).

Figure-2: BACE1 and p75 expression are enhanced following CCI in the mouse brain.

Figure-2:

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a) Schematic diagram represents CCI conducted on the left somatosensory cortex of mice at P90. b) A coronal section of mice brain stained with DAPI represents the region of implemented CCI. c) Immunostaining assay demonstrates BACE1 (green) and p75 (red) in both CCI and sham groups 72 hours after CCI. “Merge” is the combination of DAPI (blue), BACE1, and p75. White arrows indicate the cells, expressing both BACE1, and p75 within 300 μm from the injury site. The white dashes on the green channel indicate CCI region. n=6 mice, scale bar: 200 μm.

Table-1: BACE1 and p75 expression levels after 24, 48, 72, and 96 hours following CCI in the mouse brain.

BACE1 and p75 expression were quantified by immunostaining assay within 24, 48, 72, and 96 hours following CCI.

Expression╲Time 24 h 48 h 72 h 96 h
BACE1 ↑ ↑↑ ↑↑↑ ↑
p75 ↑ ↑↑ ↑↑↑ ↑
BACE1/p75 ↑ ↑↑ ↑↑↑ ↑
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To investigate if p75 and BACE1 co-expression is a general feature in the CNS (Koh and Loy, 1989), BACE1 was co-stained in the basal forebrain where endogenous p75 is known to be highly expressed. The IHC data indicated that BACE1 was not detectable in cholinergic neurons that expresses p75 (Figure-3). This experiment suggests that the ectopic expression of p75 upon injury may result in alternative signaling pathways, unlike those seen under normal conditions when p75 is not expressed.

Figure-3: The expression level of BACE1 and p75 in the mouse basal forebrain.

Figure-3:

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A coronal section of basal forebrain in mice at P90 was stained for DAPI (blue), BACE1 (green) and p75 (red). “Merge” shows the three channels combined. BF: basal forebrain, n=6 mice, scale bar: 200 μm.

Cell type specificity of BACE1 and p75 co-expression upon controlled cortical impact

To determine the cellular basis of BACE1 and p75 expression, the brain sections were stained using pan neuronal (NeuN) or astrocyte (GFAP) markers 72 hours after the CCI treatment. We found that BACE1 and p75 were co-expressed in NeuN (+) (70%) cells within 300 μm from the injury site, compared to a sham group that did not undergo TBI (Figure-4). However, BACE1 and p75 were not significantly co-expressed in GFAP (+) cells (Figure-5).

Figure-4: BACE1 and p75 expression in NeuN (+) cells after CCI in the mouse brain.

Figure-4:

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a) The immunofluorescence staining for BACE1 (green), p75 (red), and NeuN (+) (magenta) was performed in both sham and CCI groups within 72 hours following CCI experiment. “Merge” is the combination of three channels. The blue signal in “Merge” is DAPI. White arrows indicate NeuN cells. b) The graph represents the percentage of NeuN (+) cells expressing both BACE1 and p75 within 300 μm from the injury site. (n = 6 mice, student’s t-test, mean ± SEM, **p<0.01, scale bar: 50 μm)

Figure-5: BACE1 and p75 are not co-expressed in GFAP (+) cells after CCI in the mouse brain.

Figure-5:

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a) The immunofluorescence staining for BACE1 (green), p75 (red), and GFAP (+) (magenta) was performed in both sham and CCI groups within 72 hours following CCI experiment. “Merge” is the combination of three channels. The blue signal in “Merge” is DAPI. White arrows indicate GFAP cells. b) The graph demonstrates the percentage of GFAP (+) cells expressing, both BACE1 and p75 within 300 μm from the injury site. (n = 6 mice, student’s t-test, mean ± SEM, ns: not significant, scale bar: 50 μm)

BACE1 and p75 expression levels are enhanced in response to focal injury in mouse brain

To confirm if the effects of CCI are reproducible, a focal cortical injury localized on layers 1 and 2 of the cortex was applied. A laser injury was conducted using two-photon laser beam (~1 μm in size) in the mouse motor cortex (M1) (~50 μm from the pia mater) (Davalos et al., 2005; Grutzendler et al., 2002) (Figure-6 a, b). Consistent with the CCI experiment, the levels of both BACE1 and p75 were increased at 72 hours after focal injury within 200 μm from the injury lesion site. GFAP was up-regulated in response to injury and during inflammatory conditions and could be detected at the injury site (Hinkle et al., 1997). As a control for these experiments, the p75−/− mice were utilized to examine if BACE1 augmentation following injury could be associated with p75 expression. The increase in BACE1 levels did not occur in the p75−/− mice, (Figure-6 c, d) which suggests that BACE1 up-regulation is associated with p75 after injury and the regulation of both proteins following CCI is reproduced in a focal injury model.

Figure-6: BACE1 and p75 expression in response to the focal cortical injury in p75−/− and p75+/+ mice.

Figure-6:

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A schematic diagram demonstrates a focal injury induced by a two-photon laser beam through a cranial window over the motor cortex of the mouse. b) The beam was placed at the desired position for approximately 1–3 seconds to create a small injury site as indicated by a bright autofluorescence sphere (~15 μm in diameter). c) After 72 hours of laser lesion, the immunofluorescence staining for BACE1 (green), p75 (red), GFAP (magenta), and DAPI (blue) was performed in ipsilateral and contralateral sites of the p75−/− and p75+/+ mice. The contralateral was not subjected to the laser injury experiment and considered as a control for ipsilateral. d) The fluorescence intensity of p75 and BACE1 within 200 μm from the lesion was quantified and plotted. (n = 6 mice, student’s t-test, mean ± SEM, **p<0.01, ns: not significant, scale bar: 50 μm).

BACE1 level is changed in response to the transfection or deletion of p75

Furthermore, BACE1 regulation by p75 was investigated in HEK293 and SY5Y cell culture systems, which are known to express BACE1 (Zheng et al., 2015), to see if a similar effect could be reproduced. 24 hours after transfection with a p75 or mock vector constructs, BACE1 levels were measured by Western blot analysis. An increase in BACE1 levels were found following transfection of p75 in both cell lines (Figure-7 a–c). In addition, p75−/− cortical demonstrated low BACE1 expression compared to wildtype counterparts (Figure-7 d–g). For the remainder of the study SY5Y cell line was used for in-vitro investigations, as these cells express a low level of p75 (Chao et al., 1986) and have neuronal properties which are unseen in HEK293 cells.

Figure-7: The effect of p75 transfection or deletion on BACE1 levels in the SY5Y and HEK-293 cell lines and primary neurons.

Figure-7:

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Western blot analysis was conducted to detect BACE1 in SY5Y (a) and HEK-293 (b) cells transfected with 1μg, either mock vector or p75 constructs. c) The graph represents the quantification of (a) and (b). The cultured cortical neurons (DIV-III) isolated from E18 p75−/− and p75+/+ mice were subjected to immunostaining (d and e) and Western blotting (f and g) assays for BACE1 analysis. (n = 3 individual experiments, student’s t-test, mean ± SEM, *p<0.05, scale bar: 50 μm). β-actin in Western blot was used as a loading control.

p75 increases APP cleavage through BACE1 up-regulation

APP is a BACE1 substrate that has received considerable attention. The production of the Aβ peptide is initiated by BACE1 cleavage (Hardy and Higgins, 1992; Selkoe, 1991; Vassar et al., 1999). To assess the consequences of the up-regulated BACE1 by p75, the cleaved products of APP were measured in the SY5Y cells that stably express the most abundant human isoform of APP (APP695) (Pacheco-Quinto and Eckman, 2013). The APP fragment products such as sAPPβ and CTFs were consistently increased with BACE1 following transfection with 0.5 and 1 μg of a full length p75 in a dose-dependent fashion; whereas sAPPα, a non-amyloidogenic APP fragment, was diminished (Figure-8 a–d) (De Strooper and Annaert, 2000). Additionally, sAPPβ and BACE1 levels in p75−/− cortical neurons at DIV-III were concomitantly abolished (Figure-8 e–g). This evidence suggests that BACE1 function is enhanced enzymatically in response to p75 expression.

Figure-8: Amyloidogenic processing of APP in the presence and absence of p75 in the SY5Y-APP cells and primary neurons.

Figure-8:

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a) SY5Y-APP cells were transfected with 0.5 and 1 μg p75 or mock constructs and then subjected to Western blot analysis to detect p75 and BACE1 levels. Additionally, the full length and CTFs of APP were detected by C1/6.1 antibody. To detect soluble fragments of APP, the conditioned media was subjected to immunoprecipitation (IP) using m3.2 antibody. The IP and flow-through samples were then subjected to Western blot using anti-APP (22C11). The blotting signals obtained from IP and flow-through, represent the level of sAPPα and sAPPβ, respectively (Choi et al., 2009). b-d) Graphs demonstrate the quantification of (a). (n = 3 individual experiments, One-way ANOVA with Tukey test, mean ± SEM, *p<0.05, **p<0.01). e) Cortical neuronal isolated from E18 p75−/− and p75+/+ mice at DIV-III were lysed and subjected to Western blot to detect BACE1, fl.APP, and sAPPβ levels. f, g) The quantification of (e) (n = 3 individual experiments, student’s t-test, mean ± SEM, *p<0.05). fl.APP and β-actin were used as loading controls.

BACE1 transcription and promoter activity is enhanced in the presence of p75

To evaluate if the BACE1 up-regulation in response to p75 may be dependent upon transcription, BACE1 RNA levels and promoter activity was assessed in SY5Y cells transfected with p75 for 24 hours. These were then subjected to rt-qPCR to evaluate BACE1 RNA levels. BACE1 RNA was found to be enhanced in the cells expressing p75 compared to mock expression (Figure-9 a, b). Next, SY5Y cells were co-transfected with a rat BACE1 promoter luciferase construct (Figure-9 c), along with p75 or a mock vector. Cells were subjected to a luciferase assay to analyze BACE1 promoter activity. The Fas receptor was used as a negative control for p75. p75, but not the mock or Fas receptor, was found to increase the luciferase signal of BACE1 promoter (Figure-9 d). p75 transfection in a dose-dependent manner consistently increased the luciferase signal (Figure-9 e). In addition, the effects of p75 ligands including BDNF, NGF, or proNGF on BACE1 promoter activity were also tested by the luciferase assay. These ligands failed to alter BACE1 promoter activity (Figure-9 f). Moreover, transfection with cleaved fragments of p75, extracellular domain (p75ECD), or p75 c-terminal fragment (p75 CTF), which are normally generated in the cells (Forsyth et al., 2014), did not change the BACE1 promoter signal (Figure-9 g) (Forsyth et al., 2014; Kenchappa et al., 2010; Weskamp et al., 2004). These results suggest that the expression of p75 is sufficient to induce BACE1 transduction.

Figure-9: p75 enhances BACE1 transcription and promoter activity.

Figure-9:

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a, b) p75 and BACE1 mRNA levels were measured in SY5Y cells transfected with 1 μg mock or p75 using rt-qPCR. The GAPDH mRNA was measured as a loading control (n = 3 individual experiments, student’s t-test, mean ± SEM, *p<0.05, **p<0.01). c) A schematic diagram shows a rat full-length BACE1 promoter (1.54 kb) in pGL3 vector (pGL3-BACE1) used for the luciferase assay in this study. BACE1 promoter activity was measured in SY5Y cells transfected with: d) 1 μg mock, p75, or Fas receptor, e) 0, 0.25, 0.5, 1 μg p75, f) 1 μg mock or p75 plasmids and in the presence of 10 ng/ml BDNF, NGF or proNGF for 24 hours, g) p75CTF and p75ECD. Western blot analysis was conducted to demonstrate transfection efficiency of constructs. (n = 3 individual experiments, One-way ANOVA with Tukey test, mean ± SEM, *p<0.05, **p<0.01, RLU: relative light units, control: no treatment, ns: not significant).

JNK signaling, but not NF-κB, activated by p75 contributes to BACE1 expression

Previous reports suggested that NF-κB and JNK signal pathways contribute to BACE1 expression (Guglielmotto et al., 2011; Wang et al., 2015). These pathways are activated by p75 under conditions of stress and injury (Hamanoue et al., 1999; Harrington et al., 2002; Kenchappa et al., 2010). Therefore the effect of the p75 on BACE1 expression occuring through NF-κB and JNK was investigated. Considering that BACE1 promoter includes an NF-κB binding site (Figure-9 c, and 10 a) (Chen et al., 2012), we utilized a promoter construct lacking NF-κB (ΔNF-κB) (Figure-10 a) (Wang et al., 2015; Wang et al., 2013). p75 transfection enhanced the luciferase signals of both full-length and ΔNF-κB BACE1 promoters (Figure-10 b), suggesting that the NF-κB does not significantly contribute to the BACE1 regulation. Subsequently, to assess the contribution of JNK on BACE1 up-regulation through p75, the p75 transfected SY5Y cells was treated with 10 μM SP600125, an established JNK inhibitor (Ruffels et al., 2004; Saadipour et al., 2018b). Application of SP600125 reduced BACE1 promoter activity (Figure-10 c) and protein levels (Figure-10 d,e) which were enhanced by p75. Additionally, to confirm that the over-expression of p75 triggers JNK signaling pathway, the level of pJNK was measured by Western blot analysis in SY5Y cells. The results indicate that p75 transfection enhanced pJNK levels in a dose-dependent manner (Figure-10 f, g). Furthermore, the levels of activated JNK (pJNK) and BACE1 in p75+/+cultured neurons were observed to be higher than p75−/− (Figure-10 h–j). All together, these results suggest that p75 may regulate BACE1 transduction through activation of the JNK signal pathway and that NF-κB had a minimal effect.

Figure-10: JNK, but not NF-κB signaling downstream contributes to the regulation of BACE1 expression by p75.

Figure-10:

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a) A schematic diagram represents the full-length and mutant (ΔNF-κB) rat BACE1 promoter constructs. b) The promoter activity of full-length or ΔNF-κB BACE1 promoter was measured in the SY5Y cells transfected with either mock or p75 constructs. c-e) SY5Y cells were transfected with mock and p75 constructs for 24 hours and then treated with 10 μg/mL SP600125, for an additional 3 hours. The lysate was subjected to the luciferase assay (c) and Western blot analysis (d,e) to measure BACE1 promoter activity and expression levels, respectively. f,g) The level of pJNK in SY5Y cells transfected with 0, 0.5, and 1 μg of p75 plasmid was measured by Western blot analysis. SY5Y cells were exposed with U.V light for 3 hours to activate JNK and the cell lysate was used as a positive control for anti-pJNK antibody. (n = 3 individual experiments, One-way ANOVA with Tukey test, mean ± SEM, *p<0.05, **p<0.01, RLU: relative light units, cont: no treatment). h) Western blot was performed on cultured cortical neurons (DIV-III) isolated from E18 p75−/− and p75+/+ mice to measure pJNK, JNK (total), and BACE1 levels. i,j) Graphs are the quantification of (h). β-actin and JNK were considered as loading controls. (n = 3 individual experiments, student’s t-test, mean ± SEM, *p<0.05, RLU: relative light units)

Discussion

The enzymatic activity of BACE1 is influenced by several factors including splicing events and BACE1 protein levels. Thus, BACE1 is tuned by transcriptional and post-transcriptional events, as well as its degradation (Cole and Vassar, 2007). BACE1 is not only a developmental regulatory protein that contributes to neuronal growth and maturation, but it also becomes elevated under injuries and stress conditions such as ischemia and oxidative stress (Tamagno et al., 2002; Tong et al., 2005; Wen et al., 2004). Additionally, considerable attention has been given to the pathological conditions that occur with TBI and AD, where BACE1 is induced (Blasko et al., 2004; Fukumoto et al., 2002). TBI is a risk factor for AD and has been linked to APP cleavage and Aβ deposition in the brain (Johnson et al., 2010). Experimental TBI in rodents enhances BACE1 levels which results in Aβ production (Blasko et al., 2004; Loane et al., 2009; Walker et al., 2012). However, the underlying mechanisms by which BACE1 is elevated in response to injury are not fully understood. In the present study, an upstream mechanism to account for BACE1 regulation was uncovered.

p75 neurotrophin receptor like BACE1, is widely expressed in early development, and its levels are subsequently reduced during maturation (Underwood and Coulson, 2008). This study reports that p75 expression was enhanced with BACE1 in response to both CCI and focal cortical injury in adult mouse brain. Their co-expression is significant since p75 has been considered as a potential target for pharmacological control under pathological conditions. Although p75 does not have intrinsic catalytic activity, it interacts with and modulates the function of TrkA, TrkB, and TrkC as well as sortilin and Nogo receptors and contributes to a wide range of cellular functions (Bibel et al., 1999; Hempstead et al., 1991; Nykjaer et al., 2004; Saadipour et al., 2017; Wang et al., 2002).

To investigate the cellular basis of BACE1 and p75 co-expression, brain sections using pan neuronal (NeuN) or astrocyte (GFAP) marker following CCI experiment were stained. It was found that BACE1 and p75 expression in NeuN (+) cells was increased ~ 300 μm around the injury site. An increase in BACE1 level in p75+/+ but not p75−/− mice following a focal injury indicates that BACE1 is linked to p75. Other studies have also shown that p75 is highly expressed during sympathetic sprouting after a medial septal lesion (Nelson et al., 2014). In addition, other neuronal subtypes that express p75 after injury are dorsal root ganglion neurons (Zhou et al., 1996), motoneurons (Ernfors et al., 1989), corticospinal neurons (Giehl et al., 2001), cerebellar purkinje cells (Martinez-Murillo et al., 1993), and basal forebrain neurons (Oh et al., 2000). p75 is also reported to be expressed in macrophages, microglia, oligodendrocytes, astrocytes and/or Schwann cells in response to injury and neurodegenerative diseases (Beattie et al., 2002; Choi and Friedman, 2009; Dowling et al., 1999; Meeker and Williams, 2015; Taniuchi et al., 1986). However, the CCI experiment did not show a dramatic increase of BACE1/p75 co-expression in GFAP (+) cells. This could be due to the type of injury model and the region of brain that was subjected to CCI.

p75 re-expression after injury may regulate a variety of functions depending upon the type of cells are expressing p75 as well as what co-receptors and ligands interact with it. As a result, p75 may either contribute to lesion-induced plasticity that partly regulates developmental mechanisms or participate in cell death to remove defective neurons from the injury site as part of homeostatic program (Dechant and Barde, 2002; Hempstead, 2002). In order to examine if the effect of p75 on BACE1 levels is due to its ectopic expression, BACE1 was stained in basal forebrain neurons where the level of endogenous p75 is known to be as high (Koh and Loy, 1989). Despite a high expression of p75, BACE1 was not identified in these neurons under normal conditions. Our study suggests that the ectopic expression of p75 upon injury may lead to BACE1 elevation. There is evidence that the deletion of p75 from cholinergic basal forebrain neurons reduces Aβ plaque deposition and cognitive impairment in aged APP/PS1 mice; however, BACE1 was reported to be unchanged and detected at very low levels in the cortical neuronal population under normal conditions (Qian et al., 2019), which is consistent with our results. However, there are several issues that should be considered when regarding that the deletion of p75 does not have an effect on BACE1 level while overexpression of p75 under injury regulates BACE1 expression. Because the basal levels of BACE1 and p75 in cortex of adult mice are extremely low, the effect of p75 deletion on BACE1 reduction may not be observable, expect when p75 is over-expressed due to TBI. Additionally, the signaling pathways activated by over-expression of p75 under injury conditions may be different than normal conditions. Thus, a robust regulatory impact of p75 on BACE1 expression may occur preferentially under conditions of injury and stress, not under normal condition.

The BACE1 promoter contains a number of putative transcription factor binding sites including Sp1, NF-κB, YY1, MZF1, HNF-3β and four GATA sites. These are highly conserved between rodents and human which suggests that the regulatory mechanisms of BACE1 expression are common between these species (Lange-Dohna et al., 2003; Rossner et al., 2006). BACE1 transcriptional molecules, such as STAT1 (Zhao et al., 2011), STAT3 (Oliva et al., 2012; Zhao et al., 2011), HIF-1α (Anderson et al., 2009), and NF-κB, (Sanz et al., 2002) are activated following TBI. p75, as a member of the TNF receptor family, mediates nuclear translocation of the NF-κB p65 subunit (Hamanoue et al., 1999). In addition, JNK is known to be activated by p75 under injury and stress conditions. Based on this evidence, it is speculated that p75 could influence BACE1 expression through activation of NF-κB. However, our data showed that BACE1 expression is not influenced by lack of the NFκB binding site on the BACE1 promoter. In fact, the up-regulation of BACE1 gene and protein in the presence of p75 are decreased in response to JNK inhibitor, suggesting that the p75/JNK pathway could act as a potential mechanism of BACE1 regulation.

BACE1, like p75, is over-expressed in neurons and glia in response to injury, and this is associated with Aβ plaque deposition in the brain of AD patients (Cai et al., 2001; Hartlage-Rubsamen et al., 2003; Rossner et al., 2001). The accumulation of Aβ plaques in the brain is a hallmark of AD. The Aβ production is frequently initiated by BACE1 cleavage (Hardy and Higgins, 1992; Selkoe, 1991; Vassar et al., 1999). An in-vitro control experiment for BACE1 functionality demonstrates that p75 transduction enhanced BACE1 levels, as well as, amyloidogenic APP processing in the SY5Y-APP cells. Furthermore, BACE1 levels and APP cleavage are diminished in the primary cortical neurons lacking p75. This also suggests that p75 exerts influence upon BACE1 activity.

Additional experiments in cell lines and primary neuronal culture confirmed BACE1 regulation by p75. For instance, transfection of p75 construct up-regulates both BACE1 gene and protein expression, whereas p75 removal prevents BACE1 expression. Mature and pro-neurotrophin can bind to p75 (Reichardt, 2006), however using a BACE1 promoter, BACE1 transcription remained unchanged in response to these ligands. This could be due to two important reasons. First, it is reported that p75 upon over-expression can constitutively activate signaling downstream without requiring ligands (Rabizadeh et al., 1993). Furthermore, p75 can be internalized upon transfection in cells (Bronfman et al., 2003). As a result, the receptor may not be available at the membrane and treatment with the ligands may not further stimulate p75 activity. Over expression of cleaved fragments of p75 including p75ECD and CTF did not alter BACE1 promoter activity, suggesting enhanced expression of full length p75 is required to transduce signals leading to BACE1 elevation.

In conclusion, our current study uncovers a close association between p75 neurotrophin receptor and BACE1 expression which is relevant to a variety of the CNS injuries and neurological disorders. Additional insight into BACE1 and p75 proteins during injury could reveal further biomarkers and molecular mechanisms that underlie brain injury and diseases.

Figure-11: A summary diagram represents a potential underlying mechanism of BACE1 regulation upon brain injury.

Figure-11:

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The schematic diagram demonstrates that p75 neurotrophin receptor potentially contributes to the regulation of BACE1 expression through activation of JNK signaling after brain injury and SP600125, a JNK inhibitor, can prevent this effect.

Highlight.

BACE1 plays critical roles in the homeostasis of the brain, and it must be precisely regulated. This study explores a novel mechanism by which BACE1 expression is regulated upon brain injury through p75 neurotrophin receptor signaling and provides a link to traumatic brain injury and Alzheimer’s disease.

Acknowledgment

We thank Dr. Francis S. Lee (Weill Cornell School of Medicine, New York, NY) and Dr. Elizabeth Eckman (Biomedical Research Institute of New Jersey, NJ, USA) for kindly providing the p75−/− mice and SY5Y-APP695 cell line, respectively. We also thank Dr. Barbara Hempstead (Weill Cornell School of Medicine, New York, NY) for providing recombinant proNGF. This work was supported by research grant from National Institutes of Health, 2R56AG025970-11A1.

Footnotes

Conflict of Interest: The authors declare no competing financial interests.

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