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The Journal of Neuroscience, September 1, 2000, 20(17):6340-6346
Neurotrophins Induce Death of Hippocampal Neurons via the p75
Receptor
Wilma J.
Friedman
Department of Pathology, Taub Institute for the Study of
Alzheimer's Disease and the Aging Brain, and the Center for
Neurobiology and Behavior, Columbia University College of Physicians
and Surgeons, New York, New York 10032
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ABSTRACT |
Nerve growth factor (NGF) and related neurotrophins influence
neuronal survival and differentiation via interactions with the trk
family of receptors. Recent studies have demonstrated that
neurotrophins may also induce cell death via the p75 receptor. The
importance and generality of neurotrophin-induced death in the brain
have not been defined but may play a critical role during development
and in disease-associated neuronal death. Here we demonstrate for the
first time that all four members of the neurotrophin family directly
elicit the death of hippocampal neurons via the p75 receptor. The
hippocampus is a complex structure with many different neuronal
subpopulations, and signals that influence neuronal death during
development may have a critical impact on the mature function of this
structure. In these studies we show that each neurotrophin causes the
death of hippocampal neurons expressing p75 but lacking the cognate trk
receptor. Neurotrophin-induced neuronal death is mediated by activation
of Jun kinase. These studies demonstrate that neurotrophins can
regulate death as well as survival of CNS neurons.
Key words:
neurotrophins; NGF; neurotrophin receptors; p75; apoptosis; Jun kinase
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INTRODUCTION |
The neurotrophins nerve growth
factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and NT4 have been shown to play several important roles in the
development of peripheral and central neurons. One critical role is to
support the survival of many neuronal populations during the period of developmental cell death (Oppenheim et al., 1992 ). The survival effects
of neurotrophins are mediated via the trk family of receptors: TrkA,
TrkB, and TrkC. NGF binds specifically to TrkA (Hempstead et al., 1991;
Kaplan et al., 1991; Klein et al., 1991a), TrkB is a receptor for BDNF
and NT4 (Klein et al., 1991b; Ip et al., 1992), and TrkC binds NT3
(Lamballe et al., 1991). In addition, all neurotrophins bind to a
common receptor, p75, that can modify the binding and function of
neurotrophins when coexpressed with trk receptors (Lee et al., 1994;
Rydén et al., 1997). Recent studies have shown that interaction
of NGF with the p75 receptor in the absence of trk signaling can cause
cell death (Rabizadeh and Bredesen, 1994; Casaccia-Bonnefil et al.,
1996; Frade et al., 1996); however the importance of this phenomenon
for the development of CNS neurons has not been determined. The p75
receptor is more widely expressed in the CNS during development than in
the adult (Yan and Johnson, 1988), suggesting that this receptor may
have a special role during development. In particular, expression of p75 may help target neurons for developmental cell death in the CNS.
These studies demonstrate that all four neurotrophins directly elicit
the death of developing hippocampal neurons. In the hippocampus, factors that influence developmental death may have important impact on
the mature function of this structure, which is critically involved in
learning and memory.
In the adult CNS, neurons of the hippocampus produce all four
neurotrophins, which serve as target-derived factors for afferent neurons from the basal forebrain (Hefti et al., 1984; Alderson et al.,
1990; Friedman et al., 1993; Chen et al., 1997), locus coeruleus
(Friedman et al., 1993; Arenas and Persson, 1994), and other
populations. However, neurotrophins are expressed in the hippocampus
from early in development (Auburger et al., 1987; Maisonpierre et al.,
1990; Friedman et al., 1991, 1998; Ernfors et al., 1992) and may
influence local neurons before serving as target-derived factors for
afferent populations. Although p75 has not been detected in the normal
adult hippocampus (Kiss et al., 1988), it is abundantly expressed
during late embryonic and early postnatal development (Buck et al.,
1988; Lu et al., 1989), which is the period of developmental cell death
in the hippocampus (Ferrer et al., 1990; Gould et al., 1991). TrkB and
TrkC receptors are also present in the hippocampus from early in
development (Ernfors et al., 1992; Ringstedt et al., 1993), although
TrkA has not been detected in this neuronal population (Ip et al., 1993). We investigated the possibility that neurotrophins may influence
the survival or death of developing hippocampal neurons.
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MATERIALS AND METHODS |
Materials. NGF, NT3, NT4/5, and TrkB-IgG were
generously provided by Genentech (San Francisco, CA). BDNF and the NGF
triple mutant (tri-NGF) were a gift from C. F. Ibáñez (Karolinska Institute, Stockholm, Sweden). Anti-p75
IgG 192 was purchased from Chemicon (Temicula, CA), and the 9651 antiserum was generously provided by M. V. Chao (Skirball
Institute, New York University). Pan-Trk, TrkBin,
and TrkCin2 antisera were provided by David
Kaplan (Montreal Neurological Institute, Montreal, Quebec, Canada), and
CEP-1347/KT7515 was from Cephalon. Eagle's MEM, Ham's F12, and
penicillin-streptomycin were purchased from Life Technologies
(Gaithersburg, MD). Polylysine, glucose, insulin, putrescine,
progesterone, transferrin, and selenium were obtained from Sigma (St.
Louis, MO). Secondary antibodies used for immunostaining were
biotinylated goat anti-rabbit (Vector Laboratories, Burlingame, CA) or
Alexa 488 and Alexa 594 anti-rabbit and anti-mouse antibodies
from Molecular Probes (Eugene, OR) for fluorescence. The p75  / mice
(Lee et al., 1992) were generously provided by C. F. Ibáñez (Karolinska Institute).
Neuronal cultures. Pregnant rats were killed by exposure to
CO2 and soaked in 80% ethanol for 10 min.
Embryonic day 18 (E18) rat fetuses were removed under sterile
conditions and kept in PBS on ice. For experiments with mice, fetuses
were removed from E16 C57BL6 wild-type or p75 / mice (Lee et al.,
1992). Hippocampi were dissected, dissociated by trituration in
serum-free medium, plated on polylysine (0.1 mg/ml)-coated tissue
culture wells or plastic Lab-Tek slide wells, and maintained in a
serum-free environment (Friedman et al., 1993; Farinelli et al., 1998).
The medium consists of a 1:1 mixture of Eagle's MEM and Ham's F12
supplemented with glucose (6 mg/ml), putrescine (60 µM),
progesterone (20 nM), transferrin (100 µg/ml), selenium
(30 nM), penicillin (0.5 U/ml), and streptomycin (0.5 µg/ml). In all experiments neurons were cultured for 4-5 d before
treatment. Cultures contained <2% glial cells, confirmed by staining
for glial markers. The absence of glia is critical because astrocytes
in culture produce high levels of NGF.
Neuronal survival assay. Survival of cultured hippocampal
neurons was assayed by a method we adapted (Farinelli et al., 1998; Troy et al., 2000) that has been used routinely to assess
pheochromocytoma 12 (PC12) cell viability (Rukenstein et al., 1991).
After removal of the medium, cultured cells were lysed, and intact
nuclei were counted with a hemacytometer. Nuclei of dead cells either
disintegrate or, if in the process of dying, appear pyknotic and
irregularly shaped. In contrast, nuclei of healthy cells are phase
bright and have clearly defined limiting membranes. Cell counts were performed in triplicate wells. Statistical significance was determined by ANOVA with Bonferroni's post hoc analysis.
Morphological analysis. Cultured cells were fixed with 4%
paraformaldehyde, blocked for 1 hr with PBS and 5% normal goat serum, and exposed overnight at 4°C to primary antibody in PBS with 0.3% Triton X-100. Primary antisera were directed against p75 [9651, 1:1000
dilution (Huber and Chao, 1995), or 192 IgG (Chemicon), 1:1000
dilution], the intracellular domain of TrkB
[anti-TrkBin, 1:2000 (Allendoerfer et al.,
1994)], or the intracellular domain of TrkC
[anti-TrkCin2, 1:1000 (Allendoerfer et al.,
1994)], indicating the presence of the full-length TrkB and TrkC
receptors. Cells were then washed with PBS, exposed to the appropriate
biotinylated secondary antibody, and visualized by the use of the
avidin biotin-peroxidase technique (ABC Elite; Vector Laboratories).
Alternatively, for double labeling, cells were visualized by the use of
secondary antibodies coupled to different fluorophores (Alexa 488 and
Alexa 594; Molecular Probes). Controls for all immunostaining included exposing the cells to the appropriate secondary antibodies in the
absence of primary antibody. To identify dying neurons, cells were also
labeled with the Hoechst 33342 dye (1 µg/ml; Sigma) and examined by
fluorescence microscopy (Stefanis et al., 1999). Apoptotic nuclei were
identified by chromatin margination or condensation and clumping.
Immunoprecipitation and Western blot analysis. Cells were
lysed in a buffer consisting of Tris-buffered saline with 1% NP-40, 1 mM PMSF, 10 µg/ml aprotinin, 1 µg/ml leupeptin, and 0.5 mM sodium vanadate. Total protein was quantified by the
Bradford assay (Bio-Rad, Hercules, CA). For p75 immunoprecipitation,
100 µg of total protein from PC12 cell or hippocampal neuron lysates
was incubated with the monoclonal antibody 192 IgG (Chemicon) for 2 hr
on a rocking platform at 4°C. Protein A-Sepharose (Pharmacia,
Piscataway, NJ) was then added to the lysates and kept for an
additional 2 hr at 4°C. Immunoprecipitates were subjected to Western
blot analysis and probed with 9651 anti-p75 antiserum (Huber and Chao,
1995). As a control, PC12 lysates were processed as described above in the absence of immunoprecipitating antibody. For analysis of tyrosine phosphorylation of trk receptors, cells were lysed as described above,
incubated with wheat germ lectin-agarose (Pharmacia) for 2 hr at 4°C,
run on a Western blot, and probed with an anti-phosphotyrosine antibody
(Upstate Biotechnology, Lake Placid, NY). For Western analysis of
phospho-c-Jun N-terminal kinase (P-JNK), cells were washed with
PBS, harvested in SDS lysis buffer, and boiled before loading on the
gel. Blots were probed with anti-P-JNK (New England Biolabs), stripped, and reprobed for JNK (New England Biolabs).
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RESULTS |
Neurotrophins induce death of hippocampal neurons
To assess the influence of neurotrophins on developing hippocampal
neurons, primary neuronal cultures were prepared from E18 rat embryos.
The p75 receptor was highly expressed in these cultured embryonic
neurons and was not significantly regulated by short-term exposure to
the different neurotrophins (Fig.
1a). Expression of TrkA was
not detected in hippocampal neurons, whereas TrkB and TrkC were
expressed in subpopulations (Fig. 1b,c), consistent with
previous observations (Ip et al., 1993). We investigated the potential
influence of NGF in this population of CNS neurons that express p75 in
the absence of TrkA. Hippocampal neurons were grown in culture for
5 d and exposed to NGF overnight. In a dose-response relationship, 1 and 10 ng/ml NGF had no effect; however 100 ng/ml NGF
elicited a loss of 30-40% of the hippocampal neurons (Fig. 2a). The degree of neuronal
death was not increased at higher doses of NGF. This dose effectiveness
was consistent with binding to the p75 receptor. Because all
neurotrophins can bind to p75, we examined whether other neurotrophins
would elicit neuronal death in this paradigm. Surprisingly, BDNF, NT3,
and NT4 also elicited a 30-40% loss of neurons (Fig. 2a),
despite the presence of TrkB and TrkC in this neuronal population (Fig.
1b,c). In a time course analysis, loss of neurons was
detectable by 6 hr after treatment and was maximal by 24 hr (Fig.
2b). No additional neuronal loss was observed after 48 hr.
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Figure 1.
Expression of neurotrophin receptors in embryonic
hippocampal neurons after 5 d in culture. a,
Neurons were treated for 2 hr with vehicle [control
(C)] or the different neurotrophins.
Lysates were immunoprecipitated with anti-p75 (192 IgG), run on a
Western blot, and probed with anti-p75 (9651). PC12 cell lysates were
used as a positive control (+). No signal was detected in PC12 lysates
in the absence of the immunoprecipitating antibody ().
b, Hippocampal neurons were treated for 5 min with
vehicle (C) or the different neurotrophins and
analyzed for tyrosine phosphorylation of the trk proteins
(arrowhead). Phosphorylation of trk receptors was
induced by BDNF and NT4 and by NT3 treatment, indicating the presence
of TrkB and TrkC, respectively, in the neuronal cultures
(arrowhead). No TrkA phosphorylation was detected after
NGF treatment. c, Hippocampal neurons were immunostained
with antibodies against p75, TrkC, or TrkB.
Arrows indicate positively stained neurons, and
arrowheads indicate negatively stained neurons.
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Figure 2.
Neurotrophins induce the death of hippocampal
neurons. Neurons were cultured for 5 d and treated with vehicle or
neurotrophins in triplicates. Survival is reported as the percent of
intact nuclei compared with that in untreated controls and is presented
as the mean ± SEM. a, Dose-response curve for
neurotrophin-induced death of hippocampal neurons after overnight
exposure to NGF, BDNF, NT3, or NT4. Data are expressed as the percent
of control in triplicate samples from eight independent experiments
(n = 24). The mutant tri-NGF that cannot bind p75
did not elicit neuronal death. An asterisk indicates
values different from the control value at p < 0.001. b, Time course of neurotrophin-induced death of
hippocampal neurons. Neuronal loss was apparent by 6 hr of treatment
and was maximal at 24 hr. No additional cell loss was detected after
longer treatment times. Data reported are from triplicate samples from
three independent experiments (n = 9 cultures per
sample). An asterisk indicates values different
from control at p < 0.01. The apparent absence of
error bars for some samples indicates that the error was smaller than
the symbol used.
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Neurotrophin-induced death is mediated by p75
The dose-response relationship observed for the neurotrophins to
elicit neuronal death was consistent with activation of p75. To
determine the requirement for p75 binding, a mutant NGF that lacks the
ability to bind p75 (Ibáñez et al., 1992) was used and did
not elicit death (Fig. 2a). This mutant NGF retains binding to TrkA and elicited neurite outgrowth from PC12 cells similar to that
of wild-type NGF (data not shown). To confirm the role of p75 in
mediating neurotrophin-induced death, neurons were treated with
neurotrophins in the presence of a blocking antibody to p75 (9651)
(Huber and Chao, 1995; Mount et al., 1998). The presence of anti-p75
prevented the death induced by NGF, BDNF, NT3, or NT4 (Fig.
3a), demonstrating that
binding to p75 is required for neurotrophin-induced death of
hippocampal neurons. Further confirmation of the role of p75 was
obtained by culturing hippocampal neurons from p75 / mice (Lee et
al., 1992). Neurons from these mice did not die in response to
neurotrophin treatment, compared with an ~40% loss of hippocampal
neurons from wild-type mice (Fig. 3b).
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Figure 3.
p75 mediates neurotrophin-induced death.
a, Anti-p75 antiserum prevented neurotrophin-induced
death of hippocampal neurons. Cultured neurons were treated overnight
with neurotrophins (100 ng/ml) in the presence of normal rabbit serum
(1:100 dilution; open bars) or a blocking antibody to
p75 (9651; 1:100 dilution; filled bars). Data are
expressed as the percent of control in triplicate samples from four
independent experiments (n = 12). An
asterisk indicates values different from control at
p < 0.001. b, Hippocampal neurons
from p75 / mice (hatched bars) were compared with
neurons from wild-type mice (open bars) for the ability
of neurotrophins to induce death. Cultured neurons were treated with
neurotrophins (100 ng/ml) overnight. Data are expressed as the percent
of intact nuclei compared with that of untreated neurons
(n = 5 cultures per treatment), and an
asterisk indicates values different from control at
p < 0.001.
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Endogenously produced neurotrophins protect via trk signaling
BDNF, NT3, and NT4 caused a loss of hippocampal neurons despite
the presence of TrkB and TrkC in this population. Previous studies
suggested that coexpression of the cognate trk receptor abrogates a
p75-mediated death signal (Davey and Davies, 1998; Yoon et al., 1998).
Because the hippocampus is composed of a heterogeneous population of
neurons, we investigated whether specific subpopulations of hippocampal
neurons expressed p75 in the absence of TrkB or TrkC and were
selectively vulnerable to death induced by neurotrophins. In untreated
cultures, double labeling with anti-p75 (192 IgG) and a pan-trk
antiserum revealed that 40% of the neurons that expressed p75 lacked a
trk receptor. After treatment with the different factors for 6 hr,
neurons were labeled with antibodies against p75, the cognate trk
receptor (i.e., anti-TrkBin for BDNF- or NT4-treated
neurons, anti-TrkCin2 for NT3-treated neurons, or a pan-Trk
antibody for NGF-treated neurons), and the Hoechst 33342 dye to
identify apoptotic cells by nuclear morphology. Apoptotic neurons were
identified by Hoechst staining and scored for receptor phenotype (Fig.
4). Table 1
shows a comparison of the number of apoptotic neurons expressing p75 in
the absence versus the presence of a trk receptor. For all neurotrophin
treatments, 85-90% of the apoptotic neurons expressed p75 in
the absence of a trk receptor.
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Figure 4.
Neurotrophins induce apoptosis of neurons
expressing p75 in the absence of trk receptors. Hippocampal neurons
were treated with NGF (a-c), BDNF
(d-f), or NT3 (g-i) for 6 hr. All cultures were immunostained with anti-p75 (192 IgG;
a, d, g) and labeled with
Hoechst 33342 (c, f, i) to
identify the nuclei of apoptotic cells. NGF-treated cultures were
immunostained with anti-pan-Trk (b), BDNF-treated
cultures were labeled with anti-TrkBin
(e), and NT3-treated cultures were labeled with
anti-TrkCin2 (h). Chromatin
condensation, indicative of apoptosis, was detected in neurons that
expressed p75 in the absence of the relevant trk receptor
(arrowheads). Healthy nuclei in neurons expressing both
p75 and the relevant trk are indicated with arrows.
Scale bar, 20 µm.
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Our results confirmed that expression of the cognate trk receptor
primarily protected neurons from neurotrophin-induced death. In
addition, despite the absence of TrkA, the majority of p75-positive neurons that were spared from NGF-induced death were labeled with the
pan-Trk antibody (Table 1), indicating that these neurons expressed
TrkB or TrkC. Because hippocampal neurons produce neurotrophins in
culture (Friedman et al., 1998), it is possible that low concentrations of endogenously produced neurotrophins may protect neurons that express
TrkB and/or TrkC from NGF-induced death. To investigate this issue,
actions of endogenously produced BDNF and NT4 were prevented by the use
of a TrkB-IgG fusion protein. The presence of TrkB-IgG significantly
enhanced NGF-induced neuronal loss compared with NGF alone or with a
control IgG, resulting in death of almost 50% of the total neuronal
population (Fig. 5). When apoptotic neurons were identified by Hoechst staining and scored for receptor phenotype, the TrkB-expressing neuronal population specifically demonstrated increased vulnerability to NGF-induced death (Table 2), indicating an increased
susceptibility to p75-mediated death in the absence of trk signaling.
The percent of TrkC-positive neurons that were apoptotic in response to
NGF was unchanged in the presence or absence of the TrkB-IgG, as
expected (Table 2). Moreover, treatment with BDNF did not show enhanced
neuronal death in the presence of TrkB-IgG, because neurons expressing
TrkB together with p75 were still spared (Fig. 5). These data strongly
support the idea that low concentrations of endogenously produced BDNF or NT4 protect TrkB-expressing neurons from p75-mediated apoptosis and
that in the absence of TrkB signaling the vulnerability to NGF-induced
death is increased.
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Figure 5.
Blocking the actions of endogenously produced BDNF
and/or NT4 with TrkB-IgG enhances neuronal loss in response to NGF.
TrkB-IgG (10 µg/ml) was added to the cells 1 hr before the addition
of neurotrophins for overnight treatment. Data are expressed as the
percent of intact nuclei relative to that in the absence of added
neurotrophins. Open bars indicate cells in the presence
or absence of the indicated neurotrophins alone. Stippled
bars show neurons with the IgG control fragment. Hatched
bars indicate cells treated with TrkB-IgG. An
asterisk indicates values different from control at
p < 0.001; double asterisks
indicate a value different from NGF alone or the NGF + IgG control at
p < 0.01. Data reported are from triplicate
samples from two independent experiments (n = 6).
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JNK signaling mediates neurotrophin-induced death
Several signaling pathways have been suggested to mediate the
actions of p75 in different cell types, including production of
ceramide (Dobrowsky et al., 1994), activation of JNK, and induction of
the nuclear factor- B (NF-B) transcription factor (Yoon et al.,
1998). We assessed whether either NF-B or JNK was activated by
neurotrophins in hippocampal neurons. Electrophoretic mobility shift
analysis demonstrated that NF-B was not activated by NGF in
hippocampal neurons (data not shown). In contrast, Western blot
analysis demonstrated JNK phosphorylation within 10 min of NGF
treatment (Fig. 6a),
supporting the possibility that this pathway may play a role in
p75-mediated death. BDNF and NT3 treatment elicited JNK phosphorylation
as well, whereas the mutant NGF that does not bind p75 (tri-NGF)
(Ibáñez et al., 1992) did not elicit JNK phosphorylation
(Fig. 6b). Moreover, NGF-induced JNK phosphorylation was
blocked by anti-p75 (Fig. 6d). To deter-mine whether the JNK pathway plays a role in p75-mediated neuronal death, cultures were
treated with CEP-1347/KT7515 to prevent upstream activation of JNK
(Maroney et al., 1998). Treatment with CEP-1347/KT7515 blocked JNK
phosphorylation (Fig. 6c) and prevented neurotrophin-induced death of the neurons (Fig. 6e), suggesting that the JNK
pathway is essential for p75-mediated death of hippocampal neurons.
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Figure 6.
The JNK-signaling pathway mediates
neurotrophin-induced death of hippocampal neurons. a,
NGF induces JNK phosphorylation in hippocampal neurons. Neurons were
treated with NGF (100 ng/ml) for the times indicated. b,
JNK phosphorylation was also induced by BDNF and NT3 (100 ng/ml)
treatment of hippocampal neurons, but not by mutant NGF (tri-NGF) that
lacks p75 binding. Shown is a 20 min time point. c,
Cultures were treated with NGF for 20 min in the presence or absence of
CEP-1347/KT7515 (CEP). Incubation of cells with 200 nM CEP-1347/KT7515 prevented JNK phosphorylation by NGF,
whereas CEP-1347/KT7515 by itself had no effect. d,
Phosphorylation of JNK by NGF was prevented by anti-p75 (9651). Cells
were pretreated for 1 hr with anti-p75 and then exposed to NGF (100 ng/ml). A 20 min time point is shown. Blots shown in
a-d were probed for P-JNK (top panels)
and stripped and reprobed for JNK (bottom panels).
e, Prevention of JNK activation with CEP-1347/KT7515
blocked neurotrophin-induced death. Cultures were treated with
neurotrophins overnight in the absence (open bars) or
presence (hatched bars) of 200 nM
CEP-1347/KT7515. Data are expressed relative to the control number of
cells in the absence of added neurotrophins. An asterisk
indicates values different from control at p < 0.01. Data are from triplicate samples from three independent
experiments (n = 9).
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DISCUSSION |
Recent studies have indicated that neurotrophins may elicit cell
survival or cell death, depending on which receptor and signaling pathway are activated. Binding and activation of the trk family of
tyrosine kinase receptors influence the survival and differentiation of
numerous neuronal populations (Barde, 1994; Snider, 1994). Coexpression
of p75 with trk receptors can modify neurotrophin binding (Hempstead et
al., 1991; Barker and Shooter, 1994) and influence ligand
discrimination (Chao, 1994), retrograde transport (Curtis et al.,
1995), and signal transduction (Verdi et al., 1994). Moreover,
coexpression of p75 with trk receptors can modify the survival actions
of neurotrophins on peripheral sympathetic and sensory neurons (Davies
et al., 1993; Barrett and Bartlett, 1994; Lee et al., 1994; Rydén
et al., 1997). In contrast, when expressed in the absence of a trk
receptor, the binding of NGF to p75 may elicit cell death (Rabizadeh
and Bredesen, 1994; Casaccia-Bonnefil et al., 1998; Frade and Barde,
1998).
In the CNS, neurotrophin-induced cell death has been demonstrated in
the developing retina (Frade et al., 1996, 1997); however the extent to
which p75-mediated death may occur elsewhere in the CNS is unknown. In
this study we demonstrate for the first time that all four
neurotrophins can directly induce death of hippocampal neurons via the
p75 receptor. Previous studies had suggested that only NGF evoked death
via p75 (Carter and Lewin, 1997), although BDNF has been shown recently
to elicit p75-mediated death of sympathetic neurons (Aloyz et al.,
1998; Bamji et al., 1998). In these studies we show that BDNF, NT3, and
NT4 as well as NGF can elicit p75-mediated death of hippocampal
neurons. This was unexpected because of the presence of TrkB and TrkC
in this population, because trk receptor signaling has been shown to
abrogate p75-mediated death (Davey and Davies, 1998; Yoon et al.,
1998). However, we found that subpopulations of neurons that were
selectively vulnerable to death induced by BDNF, NT3, or NT4 expressed
p75 and lacked the cognate trk receptor (TrkB or TrkC). Because TrkA was not detected in any hippocampal neurons, we anticipated that all
p75-expressing neurons, including those that coexpress TrkB or TrkC,
would be vulnerable to NGF treatment. Thus, a greater degree of
neuronal loss was expected in response to NGF than to BDNF, NT3, or
NT4. However, our experiments demonstrated the same percent of cell
loss with NGF as with the other neurotrophins. The neurons spared in
NGF-treated cultures were labeled with a pan-Trk antibody, suggesting
that endogenously produced neurotrophins might activate trk receptors
and protect the cells from p75-mediated death. To confirm this
hypothesis, a TrkB-IgG fusion protein was used to bind endogenously
produced BDNF and/or NT4, thereby preventing activation of TrkB. This
treatment caused the TrkB+/p75+ population to become vulnerable to
NGF-induced death, demonstrating that in the absence of TrkB
stimulation these neurons were susceptible to p75-mediated death. Thus,
neuronal survival or death may be controlled by a balance between
signaling pathways activated by the trk or p75 receptors.
Binding of NGF to p75 has been shown to elicit production of ceramide
(Dobrowsky et al., 1994), which can act as a second messenger leading
to induction of NF-B (Schutze et al., 1992; Mathias et al., 1993) or
activation of the JNK pathway (Verheij et al., 1996). In
oligodendrocytes, NGF induced activation of both the NF-B and JNK
pathways; however it is specifically the JNK pathway that leads to cell
death (Yoon et al., 1998). Activation of JNK has been implicated in a
variety of other cell death paradigms as well (Xia et al., 1995; Chen
et al., 1996; Park et al., 1996). In these studies, activation of
NF-B by neurotrophins was not detected in hippocampal neurons;
however JNK was phosphorylated by NGF, BDNF, and NT3. JNK
phosphorylation was not induced by the mutant NGF lacking the
p75-binding site and was also prevented by the anti-p75-blocking
antibody, indicating that binding to p75 is required for neurotrophins
to activate this signaling pathway. When JNK activation was blocked by
the use of CEP-1347/KT7515, NGF-induced neuronal death was prevented,
suggesting that this pathway is essential for signaling the
p75-mediated death of hippocampal neurons.
NGF has been shown to elicit production of ceramide via p75 in
hippocampal neurons (Brann et al., 1999), leading to increased neurite
outgrowth when provided during the first 18 hr after plating. Ceramide
has been shown to have different effects on neurons at different stages
of growth and may lead to neurite growth or apoptosis (Schwarz and
Futerman, 1997). Thus, NGF may also have different effects at different
stages of neuronal growth, possibly mediated via ceramide production.
When the neurons are initially beginning to elaborate processes,
signaling via p75 apparently contributes to a growth response (Brann et
al., 1999). However, in our studies NGF was provided to the neurons
after 5 d in vitro, when the neurons had already
elaborated an extensive network of neurites. An alternative possibility
is that the effects observed on neurite outgrowth may represent a
synergy between NGF and other glial-derived factors, because the
neurons in those studies were grown in the presence of glia or
glial-conditioned media (Brann et al., 1999).
The p75 receptor is highly expressed in the hippocampus during the
period of developmental cell death (Lu et al., 1989) and is upregulated
under conditions of damage (Roux et al., 1999), suggesting a possible
role for this receptor in mediating neuronal death. The hippocampus is
critical for learning and memory, and its function is compromised in
Alzheimer's disease. Therefore defining mechanisms that contribute to
the death of these neurons has important implications for hippocampal
function. We suggest that the interaction of neurotrophins with p75 may
be a general mechanism for normal developmental cell death and possibly
for neuronal death associated with damage or disease in the CNS.
Neurotrophins have been suggested to be potential therapeutic agents
for neurodegenerative diseases; however the possibility that these
factors may elicit death in susceptible neurons while supporting
survival of other populations must be further investigated. Thus, the
actions of neurotrophins in the brain represent a balance between
survival- and death-promoting activities.
| |
FOOTNOTES |
Received Feb. 18, 2000; revised June 13, 2000; accepted June 16, 2000.
This work was supported by a grant from the National Institute of
Neurological Disorders and Stroke. I am grateful to Genentech for
providing NGF, NT3, and NT4/5, to C. F. Ibáñez for
BDNF, mutant NGF (tri-NGF), and the p75 / mice, to M. V. Chao
for the 9651 antiserum, to David Kaplan for the pan-Trk, TrkB, and TrkC
antisera, to David Shelton at Genentech for the TrkB-IgG, and
to Cephalon for CEP-1347/KT7515. I thank J. Grosman for excellent technical help and L. Greene, C. Dreyfus, and C. F. Ibáñez for valuable discussions and comments.
Correspondence should be addressed to Dr. Wilma J. Friedman, Department
of Pathology, Columbia University College of Physicians and Surgeons,
630 West 168 Street, New York, NY 10032. E-mail: wjf9{at}columbia.edu.
| |
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B. Srinivasan, C. H. Roque, B. L. Hempstead, M. R. Al-Ubaidi, and R. S. Roque
Microglia-derived Pronerve Growth Factor Promotes Photoreceptor Cell Death via p75 Neurotrophin Receptor
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M. L. Florez-McClure, D. A. Linseman, C. T. Chu, P. A. Barker, R. J. Bouchard, S. S. Le, T. A. Laessig, and K. A. Heidenreich
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A. L. Bhakar, J. L. Howell, C. E. Paul, A. H. Salehi, E. B. E. Becker, F. Said, A. Bonni, and P. A. Barker
Apoptosis Induced by p75NTR Overexpression Requires Jun Kinase-Dependent Phosphorylation of Bad
J. Neurosci.,
December 10, 2003;
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[Abstract]
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N. Spears, M. D. Molinek, L. L. L. Robinson, N. Fulton, H. Cameron, K. Shimoda, E. E. Telfer, R. A. Anderson, and D. J. Price
The role of neurotrophin receptors in female germ-cell survival in mouse and human
Development,
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T. Numakawa, H. Nakayama, S. Suzuki, T. Kubo, F. Nara, Y. Numakawa, D. Yokomaku, T. Araki, T. Ishimoto, A. Ogura, et al.
Nerve Growth Factor-induced Glutamate Release Is via p75 Receptor, Ceramide, and Ca2+ from Ryanodine Receptor in Developing Cerebellar Neurons
J. Biol. Chem.,
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Y. Zhang, Y. Hong, Y. Bounhar, M. Blacker, X. Roucou, O. Tounekti, E. Vereker, W. J. Bowers, H. J. Federoff, C. G. Goodyer, et al.
p75 Neurotrophin Receptor Protects Primary Cultures of Human Neurons against Extracellular Amyloid {beta} Peptide Cytotoxicity
J. Neurosci.,
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P. P. Roux, G. Dorval, M. Boudreau, A. Angers-Loustau, S. J. Morris, J. Makkerh, and P. A. Barker
K252a and CEP1347 Are Neuroprotective Compounds That Inhibit Mixed-lineage Kinase-3 and Induce Activation of Akt and ERK
J. Biol. Chem.,
December 13, 2002;
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A. H. Salehi, S. Xanthoudakis, and P. A. Barker
NRAGE, a p75 Neurotrophin Receptor-interacting Protein, Induces Caspase Activation and Cell Death through a JNK-dependent Mitochondrial Pathway
J. Biol. Chem.,
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C. Langevin, H. Jaaro, S. Bressanelli, M. Fainzilber, and C. Tuffereau
Rabies Virus Glycoprotein (RVG) Is a Trimeric Ligand for the N-terminal Cysteine-rich Domain of the Mammalian p75 Neurotrophin Receptor
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C. M. Troy, J. E. Friedman, and W. J. Friedman
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M. Palmada, S. Kanwal, N.J. Rutkoski, C. Gustafson-Brown, R.S. Johnson, R. Wisdom, and B.D. Carter
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A. B. Brann, M. Tcherpakov, I. M. Williams, A. H. Futerman, and M. Fainzilber
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G. Khursigara, J. Bertin, H. Yano, H. Moffett, P. S. DiStefano, and M. V. Chao
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T. Hama, M. Maruyama, R. Katoh-Semba, M. Takizawa, M. Iwashima, and K. Nara
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G. Perini, V. Della-Bianca, V. Politi, G. Della Valle, I. Dal-Pra, F. Rossi, and U. Armato
Role of p75 Neurotrophin Receptor in the Neurotoxicity by {beta}-amyloid Peptides and Synergistic Effect of Inflammatory Cytokines
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TOP
ABSTRACT
INTRODUCTION
