Beta-amyloid increases the expression level of ATBF1 responsible for death in cultured cortical neurons
© Jung et al; licensee BioMed Central Ltd. 2011
Received: 22 October 2010
Accepted: 5 July 2011
Published: 5 July 2011
Recently, several lines of evidence have shown the aberrant expression of cell-cycle-related proteins and tumor suppressor proteins in vulnerable neurons of the Alzheimer's disease (AD) brain and transgenic mouse models of AD; these proteins are associated with various paradigms of neuronal death. It has been reported that ATBF1 induces cell cycle arrest associated with neuronal differentiation in the developing rat brain, and that gene is one of the candidate tumor suppressor genes for prostate and breast cancers in whose cells overexpressed ATBF1 induces cell cycle arrest. However, the involvement of ATBF1 in AD pathogenesis is as yet unknown.
We found that ATBF1 was up-regulated in the brains of 17-month-old Tg2576 mice compared with those of age-matched wild-type mice. Moreover, our in vitro studies showed that Aβ1-42 and DNA-damaging drugs, namely, etoposide and homocysteine, increased the expression ATBF1 level in primary rat cortical neurons, whereas the knockdown of ATBF1 in these neurons protected against neuronal death induced by Aβ1-42, etoposide, and homocysteine, indicating that ATBF1 mediates neuronal death in response to these substances. In addition, we found that ATBF1-mediated neuronal death is dependent on ataxia-telangiectasia mutated (ATM) because the blockage of ATM activity by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 function in neuronal death. Furthermore, Aβ1-42 phosphorylates ATM, and ATBF1 interacts with phosphorylated ATM.
To the best of our knowledge, this is the first report that Aβ1-42 and DNA-damaging drugs increased the ATBF1 expression level in primary rat cortical neurons; this increase, in turn, may activate ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM. ATBF1 may therefore be a suitable target for therapeutic intervention of AD.
Alzheimer's disease (AD), a progressive neurodegenerative disorder of the elderly, is associated with a chronic loss of synapses and neuronal death, and is characterized by the presence of parenchymal deposits of amyloid-β peptides (Aβ), the major protein component of senile plaques [1, 2]. Accumulation of Aβ in the brain is associated with disease-causing inherited variants of the amyloid precursor protein (APP) , presenilin 1 (PS1) , presenilin 2 (PS2) , and apoplipoprotein E (APOE)  genes, and an increased extracellular Aβ level is a major cause of neuronal death in AD. In addition to genetic evidence that Aβ promotes neuronal degeneration and death in vivo [7, 8], in vitro studies show that Aβ aggregates rapidly induce neuronal death by necrosis or apoptosis [9, 10], and Aβ-induced neurotoxicity involves oxidative stress, inflammation, and perturbation of calcium homeostasis . However, the mechanisms by which neuronal degeneration and death occur in AD and whether they are induced by Aβ are not completely understood.
One focus in the mechanism of neuronal death in AD is the aberrant expression of cell-cycle-related proteins, such as cdc2, cdk4, cyclin B1, and cyclin D, which mediate cell cycle progression, in vulnerable neurons of the AD brain [11–14]; these molecules play essential roles in neuronal death associated with various paradigms of neuronal death . In addition to cell cycle progression molecules, a number of cell cycle inhibitors, such as p16 and p27 [13, 16], and tumor suppressor proteins such as p53 and BRCA1 [17, 18] are also increased in levels in the AD brain. In addition to the human AD brain, the increased expression levels of cell-cycle-related proteins were also found in transgenic mouse models of AD [19, 20]. Although it is unclear why cell-cycle-related proteins show increased in levels in the AD brain and AD mouse models, one possibility is that DNA damage induced by Aβ may increase the levels of or activate these molecules. Indeed, DNA damage was found in the AD brain, and Aβ increases Cdc25A , Cdk4, and p53  levels in primary rat neurons resulting in neuronal death. Recently, Kruman et al. have reported that cultured postmitotic cortical neurons exposed to Aβ undergo apoptosis that is dependent on tumor suppressor factor ataxia-telangiectasia mutated (ATM) activity, whereas treatment with caffeine, which is an ATM inhibitor, can exert a neuroprotective effect on cultured neurons exposed to Aβ . In this context, ATM appears to potentiate neuronal apoptosis.
AT-motif binding factor 1 (ATBF1) is a 404 kDa transcription factor that contains 4 homeodomains and 23 zinc-finger motifs  involved in transcription regulations and protein-protein interactions . We previously reported that ATBF1 is highly expressed in postmitotic neurons but not in neural progenitor cells, and it induces cell cycle arrest associated with neuronal differentiation in the developing rat brain . We also found that sublocalization of ATBF1 is regulated by phospatidylinositol-3 (PI3) kinase including ATM , indicating that ATBF1 is one of the targets of ATM. Indeed, ATM phosphorylates ATBF1 at Ser1180 in HEK293T cells exposed to 10-Gy radiation . ATBF1 also interacts with p53 to activate the p21Waf1/Cip1 promoter to trigger cell cycle arrest . It has also been reported that the ATBF1 gene is one of the candidate tumor suppressor genes for prostate and breast cancers in whose cells overexpressed ATBF1 induces cell cycle arrest [28, 29]. However, the involvement of ATBF1 in AD pathogenesis is as yet unknown.
In this study, we investigated whether ATBF1 expression is altered in the brains of Tg2576 mice similarly to other cell-cycle-related molecules, and we found an up-regulated ATBF1 expression in the brains of Tg2576 mice compared with those of age-matched wild-type mice. Moreover, our in vitro studies showed that Aβ and DNA-damaging drugs, namely, etoposide and homocysteine, increased the ATBF1 expression level in primary rat cortical neurons; this increase, in turn, may activate ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM.
ATBF1 was up-regulated in the brains of 17-month-old Tg2576 mice compared with those of age-matched wild-type mice
Aβ1-42 and DNA-damaging drugs, etoposide and homocysteine, increased ATBF1 expression level in cultured rat cortical neurons
Knockdown of ATBF1 in cultured cortical neurons protected against Aβ1-42-, etoposide-, and homocysteine-induced neurotoxicity
ATBF1 mediated apoptotic function in cultured cortical neurons against Aβ1-42-induced neurotoxicity
Overexpression of ATBF1 itself in primary cortical neurons did not induce apoptosis
ATBF1-mediated neuronal death after Aβ1-42 treatment depended on ATM
ATBF1 interacted with phosphorylated ATM
ATM was required for ATBF1 to activate the p21 promoter
Recently, cell-cycle-related molecules have been implicated as required components in the mechanisms underlying neuronal death in response to injury, stroke, and neurodegenerative diseases including AD [35–38] and transgenic mouse models of AD [19, 20]. We have previously reported that ATBF1 is highly expressed in postmitotic neurons but not in neural progenitor cells in the developing rat brain, and that its mRNA expression level is highest in the embryonic day 12.5 (E12.5) brain . Moreover, the overexpression of ATBF1 induces cell cycle arrest in mouse neuroblastoma, human prostate cancer, and human breast cancer cell lines [25, 28, 29]. These findings suggest that ATBF1 may play critical roles in cell cycle arrest and proliferation. In the present study, we found that the ATBF1 expression level in the brains of 17-month-old wild-type mice decreased compared with that in the brains of 10-month-old wild-type mice. This finding is consistent with our previous finding that ATBF1 mRNA expression level gradually decreases with increasing age in the rat brain . However, ATBF1 expression was up-regulated in the brains of 17-month-old Tg2576 mice compared with that in the brains of age-matched wild-type mice. In Tg2576 mice, diffuse plaques appear after 12 months, and their amount gradually increases with age . Therefore, we considered that the increase in ATBF1 expression level was due to Aβ, and we found that the treatment with Aβ1-42 significantly increased the expression levels of ATBF1 mRNA and protein in cultured rat cortical neurons. The increase in ATBF1 expression level in the brains of 17-month-old Tg2576 mice could be triggered by the accumulation of extracellular Aβ similar to the Aβ-mediated increase in ATBF1 expression level observed in cultured cortical neurons. In addition, the reason why ATBF1 remains increased in 17-month-old Tg2576 mice could be that Aβ induces neurons to re-enter the cell cycle and ATBF1 prevents this process from occurring.
Aβ induces oxidative DNA damage. A previous study showed that the expression level of ATBF1 is increased in gastric cancer cells treated with mitomycin-C, which can induce DNA damage in many cell types . This suggests that DNA damage might increase ATBF1 expression level. We, therefore, also examined whether treatment with DNA-damaging drugs, namely, etoposide and homocysteine, affects ATBF1 expression. Here, we found that these DNA-damaging drugs significantly increased the expression levels of ATBF1 mRNA and protein in cultured rat cortical neurons. These findings suggest that the up-regulated ATBF1 expression observed in our in vivo and in vitro experiments could be due to DNA damage induced by Aβ.
It has been reported that the consequences of DNA damage are the expression of cell-cycle-related proteins [22, 39, 40] and activation of the family of phosphatidylinositol-3 (PI3)-kinases that include the ATM protein, which is involved in the regulation of cell cycle and apoptosis by the phosphorylation of many downstream substrates [41–43]. Therefore, one possibility is that ATM could constitute a common pathway activated in neuronal apoptosis after DNA damage. Recently, we have found that ATM induces ATBF1 expression during retinoicacid-induced neuronal differentiation of P19 cells by the activation and binding of CREB to a CRE consensus site located in the ATBF1 promoter (unpublished data). It has also been reported that the ATBF1 gene is one of the target genes of ATM that phosphorylates ATBF1 at Ser1180 . These observations suggest that the activation of ATM highly correlates with the function and expression of ATBF1 as a gene regulatory factor. In this study, we observed that treatment with Aβ1-42 and etoposide rapidly posphorylates ATM at Ser 1981, and that ATBF1 interacts with pATM in cultured cortical neurons. Taken together, ATM activation induced by Aβ and DNA-damaging drugs may induce ATBF1 expression.
In this study, we also examined the effect of ATBF1 on neuronal death and apoptosis induced by Aβ1-42, etoposide, and homocysteine in cultured cortical neurons, and we found that the knockdown of ATBF1 by ATBF1 siRNA transfection significantly reduced the extent of cell death and apoptosis induced by Aβ1-42, etoposide, homocysteine. In addition, the knockdown of ATBF1 attenuated the activation of caspase-3/7. These findings suggest that the increased ATBF1 expression level may mediate apoptotic function in cultured cortical neurons against Aβ1-42-induced neurotoxicity. It has been reported that Aβ and DNA-damaging drugs induce the expression and activation of p53 which plays an important role in promoting apoptosis in cultured neurons [22, 44]. Therefore, the increased ATBF1 expression level might simultaneously activate p53 to promote cell death, because ATBF1 interacts with p53 . We also found in this study that ATBF1-mediated neuronal death is dependent on ATM signals because the blockage of ATM by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 functions in neuronal death. This finding is in agreement with our previous finding that caffeine treatment inhibits the translocalization of ATBF1 to the nucleus in P19 cells . Further studies are necessary to characterize the role of ATBF1 in AD pathogenesis such as whether ATBF1 expression is altered in the AD brain.
In conclusion, the increase in ATBF1 expression level observed in the brain of 17-month-old Tg2576 mice compared with age-matched wild-type mice could be caused by DNA damage induced by Aβ1-42, which in turn activates the ATM signaling responsible for neuronal death, indicating that ATBF1 plays an important role in neuronal death in response to Aβ1-42, etoposide, and homocystein, and it may be a useful target in the development of drugs to suppress the neuronal death induced by Aβ1-42.
Female Tg2576 mice, an animal model of amyloid deposition, overexpressing human APP695 with the Swedish mutation K670N/M671, were obtained from Taconic (Germantown, NY). All the experiments were performed in accordance with the Guidelines for Animal Experiments of the Animal Experimentation Committee of the National Center for Geriatrics and Gerontology.
Cerebral cortical neurons were obtained from E17 Sprague-Dawley rats and cultured as described previously . Briefly, embryonic brains were dissected, stripped of meninges, and minced with forceps. The minced tissue was incubated in 0.25% trypsin and 2 mg/ml DNase I in phosphate-buffered saline (PBS) at 37°C for 15 min. The fragments were then dissociated into single cells by pipetting. The dissociated cells were suspended in DMEM/F-12 medium (50:50%) containing N2 supplements and 7.5% bovine albumin fraction V, and plated onto poly-d-lysine-coated 60 mm dishes at a density of 1 × 106/ml. These cells were used on day 4 of plating for further experiments. The immortalized fibroblast cell line AT22IJE-T was originally established from primary ataxia-telangiectasia (A-T) patient fibroblasts . The cells were transfected with either the pEBS7 or pEGS7-YZ ATM vector to obtain AT22IJE-T/pEBS7 (ATM -/-) and AT22IJE-T/YZ5 (ATM +/+) cells, respectively . Cells were maintained in DMEM containing 15% fetal bovine serum (FBS), 2 mM glutamine, 100 μg/ml hygromycin B, 100 U/ml penicillin, and 0.1 mg/ml streptomycin.
RNA extraction and real-time PCR
Total RNA was isolated from primary cortical neurons using an RNeasy plus mini kit (Qiagen, Valencia, CA) following the manufacturer's instructions. Reverse transcription was performed using 1 μg of total RNA using a PrimeScript RT reagent kit (Takara, Tokyo, Japan). Real-time PCR was carried out using the SYBR Premix Ex Taq system and Thermal Cycler Dice Real-Time system (Takara). The expression of the ATBF1 gene was normalized with the corresponding amount of actin mRNA using the comparative threshold cycle method following the manufacturer's protocols. Amplification was performed using the following primers (sense and antisense): ATBF1 (5'-CAAAACTTCTGCTGCCCTTC-3' and 5'-GGCTTGTCTCAAGGTGC-TTC-3') and actin (5'-CATCCGTAAAGACCTCTATGCCAAC-3' and 5'-ATGGA-GCCACCGATCCACA-3').
The synthetic Aβ1-42 peptide was purchased from Peptide Institute (Osaka, Japan), dissolved in 0.1% NH3 to the final concentration of 1 mM, and stored at -80°C until use. To confirm the state of the Aβ1-42 peptide, we performed Western blot analysis. Briefly, a stored Aβ1-42 peptide was subjected to 16% Tris-Tricine Gel (Invitrogen) electrophoresis and transferred to polyvinylidene difluoride (PVDF) membranes (Millipore, Billerica, MA). These membranes were incubated with a primary antibody against mouse monoclonal human Aβ (6E10; Covance, Emeyryville, CA). For detection, the membrane was incubated with a horseradish-peroxidase-conjugated Ig anti-mouse antibody. Immunoreaction signals were visualized with ECL™ or ECL Plus™ Western blotting detection reagent (GE Healthcare, Piscataway, NJ) and exposed to the LAS-3000 Mini Bio-imaging Analyzer System (FUJIFILM Co., Tokyo, Japan).
Western blot analysis
The cells were washed with PBS and homogenized in lysis buffer (10 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1 mM EDTA, 1% Triton X-100) containing a protease inhibitor cocktail (Roche, Mannheim, Germany). The homogenates were rocked at 4°C for 30 min and centrifuged at 13,000 × g at 4°C for 30 min to remove cell debris. The resulting supernatant was collected and protein concentration was determined using a BCA protein assay kit (Pierce, Rockford, IL). Equal amounts of protein were subjected to 7.5% or 5-20% gradient SDS polyacrylamide gel electrophoresis, and separated products were transferred to PVDF membranes. These membranes were then blocked with 5% skim milk in 10 mM Tris-HCl (pH 7.5), 150 mM NaCl, and 0.1% Tween 20 for 1 h at room temperature or overnight at 4°C. These membranes were incubated with primary antibodies, namely, the anti-ATBF1 (AT-6) antibody (1:1000; MBL, Nagoya, Japan), anti-p53 antibody (1:1000; Cell Signaling, Cambridge, UK), anti-ATM antibody (1:1000; Gene Tex, Irvine, CA), anti-ATM kinase pS1981 antibody (1:1000; Rockland, Gilbertsville, PA), or anti-actin antibody (1:2,000; Sigma, Saint Louis, MO). The membranes were washed, and then incubated with the appropriate secondary antibody conjugated to horseradish peroxidase. Immunoreaction signals were visualized with ECL™ or ECL Plus™ Western blotting detection reagent and exposed to the LAS-3000 Mini Bio-imaging Analyzer System. Signal intensity was determined using MultiGauge software (FUJIFILM).
Endogenous ATBF1 was knocked down using predesigned Stealth™siRNA against ATBF1 (ATBF1 siRNA) and Stealth siRNA negative control (control siRNA) from Invitrogen (Carlsbad, CA). The ATBF1 siRNAs sequences are as follows: ATBF1-siRNA-1 sense (5'-UAC ACU GGU CAG ACC ACU GUC CUU G-3') and antisense (5'-CAA GGA CAG UGG UCU GAC CAG UGU -3'). ATBF1-siRNA-2 sense (5'- UAC ACU GGU CAG ACC ACU GUC CUU G-3') and antisense (5'-TAC ACT GGT CAG ACC ACT GTC CTT G-3'). The primary cultured neurons were transiently transfected with 50 nM ATBF1 siRNA or with control siRNA using Lipofectamine RNAiMAX (Invitrogen) in accordance with the manufacturer's instructions. The knockdown effects were examined after 48 h of incubation. The cultures were then processed for Western blot analysis, cell viability analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay 16 h after Aβ1-42 treatment.
Cell viability analysis
Neuronal viability was evaluated by CellTiter-Glo luminescent cell viability assay (Promega, Madison, WI), which is a method to determine the number of viable cells in culture based on the quantitation of ATP present, which indicates the presence of metabolically active cells. Briefly, primary cortical neurons were seeded onto poly-d-lysine-coated 96-well plates, and incubated for 72 h. For the ATBF1 knockdown experiment, the cells were transfected with ATBF1 siRNA or with control siRNA for 48 h as described above, cells were then treated with Aβ1−42, etoposide, or homocysteine at indicated doses for 16 h. After treatment, a volume of CellTiter-Glo Reagent was added to each well equal to the volume of cell culture medium. Then, the contents were mixed for 2 min on a shaker to induce cell lysis and the plates were incubated at room temperature for 10 min in the dark. Cellular luminescence intensity was measured using a GLOMAX 96-microplate luminometer (Promega).
The ATBF1 expression vector of an 11 kb full-length human cDNA  was inserted into the pCI vector (Promega) with an HA-tagged sequence at the 5'-terminus of the inserted sequence (HA-ATBF1) . The 2.4 kb fragment upstream from the TATA-box of the human p21 (Waf1/Cip1) genomic fragment was subcloned into the basic luciferase reporter pGV-B vector (Toyo Ink Co., Ltd., Tokyo, Japan) .
Apoptosis was assessed by TUNEL using an ApopTag Fluorescein Direct In Situ Apoptosis Detection kit in accordance with the manufacturer's instructions (Chemicon, Temecula, CA). Briefly, cells were fixed with 1% paraformaldehyde in PBS for 10 min at room temperature and permeabilized in EtOH:acetic acid (2:1) for 5 min at -20°C. Cells were then washed with PBS. Fluorescein-conjugated nucleotide and TdT enzyme were added to the cells, which were then incubated for 1 h at 37°C. Nuclei were stained with DAPI. Images were obtained using an AX70 fluorescence microscope (Olympus). The percentage of apoptotic cells was determined as the ratio of the number of DAPI-TUNEL-double-positive cells with respect to the total number of DAPI-positive cells. For the overexpression of ATBF1 in cultured cortical neurons, the neurons were transiently transfected with 0.5 μg HA-ATBF1 using FuGENE HD (Roche) in accordance with the manufacturer's instructions. Twenty-four hours after transfection, TUNEL was performed as described in above. After TUNEL, the neurons were incubated with the primary antibody against HA-tag (MBL) for 1 h at RT. The secondary antibody was Alexa-594-conjugated goat anti-rabbit IgG (Molecular Probes). Images were obtained using an AX70 fluorescence microscope (Olympus).
Caspase-3/7 activity assay
Caspase-3/7 activity was assayed using a Caspase-Glo™ 3/7 assay kit (Promega), in accordence with the manufacturer's instructions. Briefly, primary cortical neurons were seeded on 96-well plates at a density of 1 × 106 cells/ml. After 3 days, the cells were treated with Aβ1-42 or DNA-damaging drugs. Caspase-Glo™ 3/7 reagent was then added to each well, and the plates were incubated at room temperature for 1 h. Cellular luminescence was measured using a GLOMAX 96-microplate luminometer (Promega).
Primary cortical neurons were grown in 10 cm dishes. After reaching 50-70% confluence, the cells were treated with 10 μM Aβ1−42 or 1 μM etoposide for an indicated time. After incubation, the cells were washed twice with PBS, lysed in 1 ml of lysis buffer (10 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1 mM EDTA, 1% Triton X-100, 50 mM NaF, and 100 uM sodium orthovanadate) containing protease inhibitor cocktail, and centrifuged at 13,000 × g at 4°C for 20 min. The resulting supernatant was immunoprecipitated overnight with a specific antibody against ATBF1 (AT-6) in the presence of protein G beads (Pierce) at 4°C. The immune complexes were washed four times with lysis buffer. The samples were subjected to 5-20% gradient SDS polyacrylamide ge electrophoresis, and separated products were transferred to a PVDF membrane and subjected to immunoblotting with a specific antibody against phosphorylated-ATM (pATM) at Ser 1981.
X-ray irradiation and p21 promoter assay
ATM (+/+) and ATM (-/-) cells were transfected with p21 promoter-luciferase, pRL-TK-luciferase (as an internal control), and an indicated dose of the HA-ATBF1 vector or pCI-HA vector as the control using Lipofectamine 2000 (Invitrogen) in accordance with manufacturer's instructions. After 24 h, the cells were irradiated with X-ray at 2.5 Gy using a Softex M-80WE X-ray generator (SOFTEX, Japan) operating at 80 kv and 10 mA for 25 min with a copper shield. Nonirradiated dells were used as control. After 12 h, luciferase activity was measured using the Dual Luciferase Reporter Assay system (Promega) in accordance with the manufacturer's instructions.
Statistical analysis was performed using a statistical package, GraphPad prism software (GraphPad Software, San Diego, CA). All values are presented as the mean ± SEM of at least three independent experiments.
AT-motif binding factor-1
Αmyloid precursor protein
Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.
We thank Eri Arata for technical assistance in Western blot analysis. We thank Makoto Nakanishi for providing the p21 (Waf1/Cip1) promoter DNA fragment. This work was supported by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (CGJ) and a grant from the Japan Health Sciences Foundation for the Research on Publicly Essential Drugs and Medical Devices (MM, KHC1104) and a grant from The Research Funding for Longevity Sciences (21-A11) from National Center for Geriatrics and Gerontology (NCGG) (CGJ and MM), Japan and a Grant-in-Aid from the Japan Science and Technology Agency (YM).
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