Brain, Vol. 125, No. 9, 2036-2043,
September 2002
© 2002 Guarantors of Brain
Aß 17–42 in Alzheimer’s disease activates JNK and caspase-8 leading to neuronal apoptosis
0 Molecular Neurobiology Unit, Laboratory of Cellular and Molecular Biology, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
Correspondence to: J. W. Kusiak PhD or Wanli Wei PhD MD, Molecular Neurobiology, Laboratory of Cellular and Molecular Biology, Intramural Research Program, GRC, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224-6825, USA E-mail: jk133r{at}nih.gov or wanliwei{at}hotmail.com
Received December 18, 2001. Revised March 26, 2002. Accepted April 14, 2002.
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Summary |
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The p3 peptide [amyloid ß-peptide (Aß) 17–40/42], derived by
- and 
-secretase cleavage of the amyloid precursor protein (APP), is a major constituent of diffuse plaques in Alzheimer’s disease and cerebellar pre-amyloid in Down’s syndrome. However, the importance of p3 peptide accumulation in Alzheimer’s disease and its toxic properties is not clear. Here, we demonstrate that treatment of cells with Aß 17–42 leads to apoptosis in two human neuroblastoma cell lines, SH-SY5Y and IMR-32. Aß 17–42 activated caspase-8 and caspase-3, induced poly(ADP-ribose) polymerase cleavage, but did not activate caspase-9. Selective caspase-8 and caspase-3 inhibitors completely blocked Aß 17–42-induced neuronal death. Aß 17–42 moderately activated c-Jun N-terminal kinase (JNK); however, overexpression of a dominant-negative mutant of SEK1, the upstream kinase of JNK, protected against Aß 17–42 induced neuronal death. These results demonstrate that Aß 17–42 induced neuronal apoptosis via a Fas-like/caspase-8 activation pathway. Our findings reveal the previously unrecognized toxic effect of Aß 17–42. We propose that Aß 17–42 constitutes an additional toxic peptide derived from APP proteolysis and may thus contribute to the neuronal cell loss characteristic of Alzheimer’s disease. Keywords: Alzheimer’s disease; p3 peptide; apoptosis; caspase; JNK
Abbreviations: Aß= amyloid ß-peptide; APP = amyloid precursor protein; ELISA = enzyme-linked immunosorbent assay; JNK = c-Jun N-terminal kinase; PARP = poly(ADP-ribose) polymerase
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Introduction |
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Alzheimer’s disease is a neurological disorder associated with memory loss, spatial disorientation and deterioration of intellectual capacity. A prominent pathological feature of Alzheimer’s disease is the presence of extracellular senile plaques that are composed of structurally abnormal neuronal processes and amyloid ß-peptide (Aß). Aß peptides are derived from the longer amyloid precursor protein (APP) by two mutually exclusive proteolytic pathways. In one, sequential cleavage of APP by ß- and
-secretases generates the amyloidogenic fragments Aß 1–40/42. In the second, cleavage by - and -secretases generate purported non-amyloidogenic Aß 17–40/42 peptides, also known as p3 fragments (Iversen et al., 1995
; Selkoe, 2001). In addition to Aß 1–40/42, plaques also contain p3 fragments. Immunohistochemical studies have shown that p3 is prevalent in selected areas of Alzheimer’s disease brains and in a subset of dystrophic neurites, but it is absent or sparse in age-matched non-Alzheimer’s disease brains (Higgins et al., 1996). Numerous studies have demonstrated that Aß 1–42 is toxic to neurones and activates microglia and astrocytes (Akama et al., 1998; Combs et al., 2001; Selkoe, 2001). However, the potential pathological role of p3 fragments in Alzheimer’s disease aetiology has not been studied extensively.
p3 is a major constituent of cerebellar preamyloid and also is present in neuritic plaques in Down’s syndrome (Gowing et al., 1994; Lalowski et al., 1996). Down’s syndrome is a genetic disease caused by the presence of an additional copy of chromosome 21. Thus, Down’s syndrome patients have three copies of the APP gene, overexpress APP in the brain and develop Alzheimer’s disease at an early age (Petronis, 1999; Neve et al., 2000). In Alzheimer’s disease and Down’s syndrome, it is believed that disruption of the normal function of APP including overexpression or altered processing of APP is the most likely explanation for amyloid plaque formation and subsequent neuronal loss and dementia (Petronis, 1999). However, the importance of p3 accumulation in Alzheimer’s disease and Down’s syndrome and its function are not clear. In this study, we examined the toxic effects of p3 and investigated the signal transduction pathway activated by p3. The results of our experiments demonstrate that treatment of cells with the p3 fragment Aß 17–42 induced c-Jun N-terminal kinase (JNK) phosphorylation, activated a Fas-like/caspase-8 cascade and led to neuronal apoptosis. The results suggest that activation of JNK and caspase-8 play an important role in Aß 17–42-induced neuronal apoptosis.
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Materials
Media and N2 supplements for cell culture were from Invitrogen (Carlsbad, CA, USA). p3 and Aß peptides including Aß 17–40, Aß 17–42, Aß 25–35, Aß 1–40, Aß 1–42 and Aß 42–1 were purchased from Biosource International (Camarillo, CA, USA). Aß 17–40 and Aß 17–42 peptides were dissolved in 10 mM HCl at 1 mM and used immediately. Aß 1–40, Aß 1–42 and Aß 42–1 were dissolved in hexafluoroisopropanol and dried under a stream of argon gas. The dried peptides were then dissolved in water at 1 mM and incubated at 37°C for 48–72 h before use. Aß 25–35 was dissolved in water and incubated at 37°C for 24 h before use. Hoechst 33342 was obtained from Molecular Probes (Eugene, OR, USA). Anti-caspase-3, anti-caspase-8 and anti-poly(ADP-ribose) polymerase (PARP) antibodies were purchased from BD PharMingen (San Diego, CA, USA); anti-cleaved-caspase-3, anti-cleaved PARP and anti-caspase-9 were purchased from Cell Signaling Technology (Beverly, MA, USA). Anti-JNK1 antibody was obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Anti-phospho stress activated protein kinase (SAPK)/JNK was purchased from Promega (Madison, WI, USA). The caspase inhibitors z-VAD-fmk, DEVD-fmk, IETD-fmk and LEHD-fmk were purchased from Enzyme Systems Products (Livermore, CA, USA).
Cell cultures and transfection
Undifferentiated SH-SY5Y human neuroblastoma cells were grown in 50% Eagle’s minimum essential medium (MEM)/50% F-12 nutrient mixture with 10% fetal bovine serum (FBS), 1 x non-essential amino acid solution and 1 x antibiotic-antimycotic (100 units/ml penicillin, 100 µg/ml streptomycin and 2.5 µg/ml Fungizone) at 37°C under 5% CO2/95% air. IMR-32 human neuroblastoma cells were grown in Dulbecco-modified essential medium (DMEM) with 10% FBS and 1 x antibiotic-antimycotic. Cells were treated with various peptides in serum free media containing N2 supplements. Transfections were performed with LipofectAmine (Invitrogen) according to the manufacturer’s protocol. SH-SY5Y cells were transfected with either pcDNA3.zeo or pcDNA.zeo-SEK1-AL constructs, kindly provided by Dr James R. Woodgett, Ontario Cancer Institute, Toronto, Ontario, Canada. SEK1-AL encodes a dominant negative form of SEK1 containing a double mutation (S220A and T224L) (Yan et al., 1994). Pooled cells stably expressing pcDNA3.zeo or pcDNA.zeo-SEK1-AL were selected in media containing 200 µg/ml Zeocin (Invitrogen) for 2 months.
Assessment of cell viability and apoptosis assays
Cell viability was evaluated using Trypan blue exclusion—counting the number of dead (blue) and live cells in the cultures after p3 peptide treatment for 48 h. A cell death detection enzyme-linked immunosorbent assay (ELISA) kit (Roche Molecular Biochemicals, Indianapolis, IN, USA) was used to detect apoptosis after p3 peptide treatment of cells for 48 h. The assay is based on a quantitative sandwich ELISA principle using antibodies directed against DNA and histones to detect mono- and oligonucleosomes in the cytoplasm of cells undergoing apoptosis. The ELISA was carried out according to the manufacturer’s protocol. For Hoechst staining, cells were treated with p3 peptides for 48 h. Fresh media containing 10 µM Hoechst 33342 was added for 20 min before the cells were photographed by fluorescence microscopy. Apoptotic cells were identified by the appearance of condensed and fragmented nuclei.
Immunoblot analysis
Cells were harvested in 300 µl of lysis buffer [20 mM HEPES, pH 7.4, 2 mM EGTA, 50 mM ß-glycerolphosphate, 1% Triton X-100, 10% glycerol, 1 mM dithiothreitol (DTT), 1 mM phenylmethylsulfonyl fluoride (PMSF), 10 µg/ml leupeptin, 10 µg/ml aprotinin, 1 mM Na3VO4 and 5 mM NaF]. The resulting lysates were resolved on 4–12% NuPAGE Bis–Tris gels (30 µg/lane; Invitrogen) and trans ferred to polyvinylidene difluoride membranes (Millipore, Bedford, MA, USA). The membranes were blocked in TBST (10 mM Tris–HCl, pH 7.4, 150 mM NaCl, 0.1% Tween-20) containing 5% non-fat milk and then probed with different antibodies. Proteins were detected by using enhanced chemiluminescence reagents (Amersham Pharmacia Biotech, Piscataway, NJ, USA).
Measurement of cellular caspase activity
Treated cells were harvested in cell lysis buffer (50 mM HEPES, pH 7.4, 1 mM DTT, 0.1 mM EDTA, 0.1% CHAPS and 0.1% Triton X-100). IETD-p-nitroanilide and LEHD-p nitroanilide were the substrates for caspase-8 and caspase-9, respectively. The experiments were performed according to the manufacturer’s protocol (Biosource International).
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Induction of neuronal apoptosis by the p3 peptide Aß 17–42
To determine the toxicity of p3 peptides, SH-SY5Y and IMR-32 cells were treated with Aß 17–40 or 17–42 for 48 h and cell death was measured by Trypan blue exclusion. Aß 17–42 dose-dependently killed cells with a maximum cell death of 40% at 30 µM; Aß 17–40 was less toxic (
20% cell death at 30 µM) in this assay (Fig. 1A and B, upper panels). A cell death detection ELISA, which measures cytoplasmic oligonucleosomes, was used to evaluate apoptosis. Aß 17–42 treatment caused 4-fold increase in absorbance values while Aß 17–40 only increased absorbance by 50% (Fig. 1A and B, lower panels). The amount of cell death caused by Aß 17–42 treatment of SH-SY5Y cells was similar to the amount caused by equivalent concentrations of Aß 1–42 and 25–35 (Fig. 1C). Aß 25–35 is a non-physiological fragment of full-length Aß peptides. It has toxic properties similar to full-length peptides. In contrast, control peptides Aß 42–1 (Fig. 1C) and Aß 35–25 (data not shown) were not toxic. For subsequent experiments therefore, we focused on the effects of Aß 17–42.
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SH-SY5Y cells exhibit a pyramidal shape with several processes extending from each cell when grown in complete media or serum-free media containing N2 supplements. After treatment with Aß 17–42, the cells exhibited a shrunken morphology with rounded cell bodies and retracted processes (Fig. 1Db). Cell cultures treated with Aß 17–42 exhibited numerous highly condensed and fragmented nuclei as measured by Hoechst 33342 fluorescent labelling, while nuclei of untreated cells were more homogeneously labelled (Fig. 1Dd). These results suggest that Aß 17–42 caused neuronal cell death mainly by apoptosis.
Involvement of caspase activation in Aß 17–42-induced apoptosis
The general caspase inhibitor z-VAD was used to determine whether Aß 17–42-induced cell death involves activation of a caspase cascade. Treatment of cells with 100 µM z-VAD completely prevented apoptotic cell death induced by Aß 17–42 (Fig. 2A). Furthermore, z-VAD also prevented the cleavage of PARP induced by Aß 17–42 (Fig. 2B). The apoptotic cell death induced by Aß 1–42 was also prevented by z-VAD, suggesting that both peptides induced cell death in a caspase-dependent manner.
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Caspase-3 is a key executioner caspase in apoptotic cell death (Fernandes-Alnemri et al., 1994
; Strasser et al., 2000). We examined whether Aß 17–42 treatment of SH-SY5Y cells activated caspase-3 by using western blotting with an antibody specific for the activated/cleaved fragment of this protein. We detected a time-dependent increase in cleaved fragments of caspase-3 after treatment of the cells with 20 µM Aß 17–42 (Fig. 3A). Treatment of cells with a specific caspase-3 inhibitor, DEVD, prevented cell death induced by Aß 17–42 (Fig. 3B) and blocked both caspase-3 and PARP cleavage (Fig. 3C).
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Caspase-8 and caspase-9 are two key initiators of distinct caspase signalling pathways (Nijhawan et al., 2000
). In order to investigate their involvement in Aß 17–42-induced apoptosis, caspase-8 and caspase-9 activities were measured colorimetrically using IETD-p-nitroanilide or LEHD-p-nitroanilide as substrates, respectively, in lysates of cells treated with Aß 17–42. Caspase-8 activity increased 2-fold after 18 h treatment with Aß 17–42 (Fig. 4B). Western blot analysis showed a decrease in full-length caspase-8 protein after 18 and 24 h treatment with Aß 17–42 (Fig. 4A). IETD, a specific inhibitor of caspase-8, protected cells completely from Aß 17–42-induced cell death (Fig. 4C). In contrast, we did not detect either significant increases in caspase-9 activity (Fig. 4B) or decreases in full-length caspase-9 protein (data not shown) in cells treated with Aß 17–42. The specific caspase-9 inhibitor, LEHD, exhibited 30% protection against Aß 17–42-induced cell death (Fig. 4C), possibly reflecting non-specific inhibition of other caspases. These results suggest that caspase-8 activation plays an important role in Aß 17–42-induced apoptosis in SH-SY5Y cells.
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Involvement of JNK activation in Aß 17–42-induced apoptosis
JNK is a stress-activated protein kinase (Hibi et al., 1993
). Activation of JNK plays an important role in apoptosis induced by several types of cell stress (Estus et al., 1994; Sanchez et al., 1994; Ham et al., 1995; Mesner et al., 1995; Xia et al., 1995; Namgung and Xia, 2000). In order to evaluate the role of JNK activation in Aß 17–42-induced apoptosis, lysates of Aß 17–42-treated cells were analysed by western blot with a specific phospho-JNK antibody. Aß 17–42 treatment of cells rapidly induced JNK phosphorylation in a biphasic manner with an initial peak at 5 min and a second peak at 1.5–6 h (Fig. 5A). To determine whether JNK activation was important in Aß 17–42-induced cell death, we measured the cell viability in SH-SY5Y cells stably transfected with HA-tagged SEK1-AL, a dominant interfering form of SEK1, the kinase upstream of JNK (Sanchez et al., 1994). Expression of SEK1-AL was confirmed by western blot analysis (data not shown). Overexpression of this dominant negative form of SEK1-AL protected cells from Aß 17–42-induced cell death by 50–60% compared with cells transfected with vector alone (Fig. 5B). These results are consistent with the view that JNK activation is an important and early event in the induction of apoptosis by Aß 17–42.
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Discussion |
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This study examined the toxic properties of p3 fragments derived from the so-called ‘non-amyloidogenic pathway’ of APP processing. We demonstrated that treatment with the p3 fragment Aß 17–42 caused the death of SH-SY5Y and IMR-32 human neuroblastoma cells. This death was apoptotic by several criteria including shrunken cell bodies, condensed and fragmented chromatin, and increased amounts of cytoplasmic oligonucleosomes as measured by ELISA. The potency of Aß 17–42 was similar to that of Aß 1–42 and Aß 25–35, while Aß 17–40 was less toxic to cells (similar to Aß 1–40). Our results suggest that a caspase cascade consisting of the initiator caspase-8 and the executioner caspase-3 is an important pathway in Aß 17–42-induced apoptosis. Furthermore, JNK activation was an early, important event in Aß 17–42-induced death. These results suggest that Aß 17–42 has in vitro toxic properties and thus may partially contribute to neuronal loss in Alzheimer’s disease and Down’s syndrome.
Like Aß, p3 is secreted from cells and deposited in brain parenchyma, accumulating predominantly in fleecy, diffuse amyloid deposits (Motte and Williams, 1989), and also in some senile plaques (Higgins et al., 1996). Aß 17–42 is also the major component of amyloid plaques in the cerebellum of Down’s syndrome patients. In an aged canine model of Alzheimer’s disease, Aß 17–42 and other N-terminal truncated Aß peptides terminating at amino acid 42 are the major components of preamyloid (Wisniewski et al., 1996). The brain levels of p3 and similarly N-truncated Aß peptides relative to full length peptides are not known. In familial forms of Alzheimer’s disease, mutations in presenilins and APP lead to an increase in the relative amount of Aß peptides ending at amino acid 42, including the p3 fragment Aß 17–42. In vitro, the p3 fragment Aß 17–42 can form a ß-sheet conformation and is highly fibrillogenic (Pike et al., 1995). Our demonstration that Aß 17–42 is toxic in vitro is in keeping with an earlier report (Pike et al., 1995) showing that an N-terminal deleted Aß peptide lacking the first 16 amino acids (i.e. p3) enhanced aggregation of the peptide and caused death of primary hippocampal neurones. However, in that report, the type of cell death caused by p3 was not determined. Our results showed that Aß 17–42 caused apoptosis in both SH-SY5Y and IMR-32 cells. Interestingly, a recent study has shown that p3 also induces cytokine production in mouse microglial cells similar to Aß 1–42 (Szczepanik et al., 2001). Taken together, these findings strongly suggest that p3 peptides have a role in neuronal death and in the enhanced inflammatory response in Alzheimer’s disease and Down’s syndrome.
Several reports have shown that caspase activity is increased in animal models of Alzheimer’s disease and in brains of Alzheimer’s disease patients (Selznick et al., 1999; Masumura et al., 2000). A growing body of evidence suggests that caspase activation plays an important role in Aß-induced cell death (Harada and Sugimoto, 1999; Giovanni et al., 2000; Allen et al., 2001; Troy et al., 2001). However, the caspase cascade involved in p3-induced neuronal death is unclear. Our results showed that Aß 17–42-induced apoptosis in SH-SY5Y cells was mediated predominantly by a caspase-8 and caspase-3 pathway. Importantly, specific inhibitors of these caspases completely prevented Aß 17–42-induced apoptosis, strongly suggesting that these caspases are critical in SH-SY5Y cell death. We were unable to detect caspase-9 activity after a 48 h treatment period, suggesting that Aß 17–42 mainly activated a Fas–Fas ligand/caspase-8 signalling pathway rather than a mitochondrial cytochrome c/caspase-9 pathway leading to neuronal apoptosis. These findings are in good agreement with the recent observation by Allen and colleagues (Allen et al., 2001) that Aß-induced neuronal death was mediated by caspase-8 and might involve a Fas-like death receptor. However, our results do not exclude the possibility that other caspases may be involved in Aß 17–42-induced neuronal apoptosis.
Neuronal cellular signalling cascades activated by p3 treatment had not been previously reported. This is the first demonstration that Aß 17–42 treatment of SH-SY5Y cells leads to early activation of JNK (within 5 min and a second peak of activity at 1.5–6 h). This rapid activation of JNK suggested that p3 may act through a receptor-mediated response. The delayed activation of JNK may be caused by reactive oxygen species induced by Aß 17–42, since oxidative stress is known to activate JNK. Overexpression of a dominant-negative SEK1-AL (MEKK4) protected cells from Aß 17–42-induced cell death by 60%. These results suggest that JNK activation plays a critical role in p3-induced neuronal apoptosis. We recently showed that Aß 1–42, like Aß 17–42, also activates JNK in SH-SY5Y cells. Overexpression of a dominant-negative SEK1 blocked Aß 1–42-induced cell death, suggesting that both Aß 17–42 and Aß 1–42 have similar modes of action (Wei et al., 2002). Other evidence has also shown that JNK and c-Jun are activated in degenerating and apoptotic neurones in Alzheimer’s disease brain (Anderson et al., 1996; Marcus et al., 1998; Shoji et al., 2000; Zhu et al., 2001). JNK is potently and preferentially activated in response to a variety of stress signals including growth factor withdrawal, -irradiation and TNF- (tumour necrosis factor alpha) or Fas ligand treatments (Chen et al., 1996). JNK activation also is associated with the induction of apoptosis (Estus et al., 1994; Ham et al., 1995; Verheij et al., 1996; Le Niculescu et al., 1999; Namgung and Xia, 2000;). Thus, these findings suggest that Aß 17–42 activated JNK may lead to upregulation of apoptosis-associated gene expression and trigger a caspase cascade leading to apoptotic cell death.
In summary, we have demonstrated that p3 peptide is toxic to neurones in vitro. The results suggested that p3 fragment Aß 17–42 should be considered a potential toxic product of APP -secretase processing. The results also raise a cautionary note about shifting APP processing to the -secretase pathway as a method of decreasing ß-secretase amyloidogenic processing of APP as a therapeutic approach in Alzheimer’s disease.
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Acknowledgements |
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We wish to thank Dr Myriam Gorospe for helpful discussions. This research was funded by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.
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A. Schmechel, H. Zentgraf, S. Scheuermann, G. Fritz, R. Pipkorn, J. Reed, K. Beyreuther, T. A. Bayer, and G. Multhaup Alzheimer {beta}-Amyloid Homodimers Facilitate A{beta} Fibrillization and the Generation of Conformational Antibodies J. Biol. Chem., September 12, 2003; 278(37): 35317 - 35324. [Abstract] [Full Text] [PDF]
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S. H. Dho and K.-S. Kwon The Ret Finger Protein Induces Apoptosis via Its RING Finger-B Box-Coiled-coil Motif J. Biol. Chem., August 22, 2003; 278(34): 31902 - 31908. [Abstract] [Full Text] [PDF]
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A. M. Minogue, A. W. Schmid, M. P. Fogarty, A. C. Moore, V. A. Campbell, C. E. Herron, and M. A. Lynch Activation of the c-Jun N-terminal Kinase Signaling Cascade Mediates the Effect of Amyloid-{beta} on Long Term Potentiation and Cell Death in Hippocampus: A ROLE FOR INTERLEUKIN-1{beta}? J. Biol. Chem., July 18, 2003; 278(30): 27971 - 27980. [Abstract] [Full Text] [PDF]
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