Abstract
The amyloid precursor like protein-1 (APLP1) belongs to the amyloid precursor protein family that also includes the amyloid precursor protein (APP) and the amyloid precursor like protein-2 (APLP2). Though the three proteins share similar structures and undergo the same cleavage processing by α-, β- and γ-secretases, APLP1 shows divergent subcellular localization from that of APP and APLP2, and thus, may perform distinct roles in vivo. While extensive studies have been focused on APP, which is implicated in the pathogenesis of Alzheimer’s disease, the functions of APLP1 remain largely elusive. Here we report that the expression of APLP1 in Drosophila induces cell death and produces developmental defects in wing and thorax. This function of APLP1 depends on the transcription factor dFoxO, as the depletion of dFoxO abrogates APLP1-induced cell death and adult defects. Consistently, APLP1 up-regulates the transcription of dFoxO target hid and reaper-two well known pro-apoptotic genes. Thus, the present study provides the first in vivo evidence that APLP1 is able to induce cell death, and that FoxO is a crucial downstream mediator of APLP1’s activity.
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References
Beckman M, Iverfeldt K (1997) Increased gene expression of beta-amyloid precursor protein and its homologues APLP1 and APLP2 in human neuroblastoma cells in response to retinoic acid. Neurosci Lett 221(2–3):73–76
Kuan YH et al (2006) PAT1a modulates intracellular transport and processing of amyloid precursor protein (APP), APLP1, and APLP2. J Biol Chem 281(52):40114–40123
Lenkkeri U et al (1998) Structure of the human amyloid-precursor-like protein gene APLP1 at 19q13.1. Hum Genet 102(2):192–196
Adlerz L et al (2003) Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction. Brain Res Mol Brain Res 119(1):62–72
Kaden D et al (2009) Subcellular localization and dimerization of APLP1 are strikingly different from APP and APLP2. J Cell Sci 122(Pt 3):368–377
Li Q, Sudhof TC (2004) Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1. J Biol Chem 279(11):10542–10550
Kume H, Maruyama K, Kametani F (2004) Intracellular domain generation of amyloid precursor protein by epsilon-cleavage depends on C-terminal fragment by alpha-secretase cleavage. Int J Mol Med 13(1):121–125
Pastorino L et al (2004) BACE (beta-secretase) modulates the processing of APLP2 in vivo. Mol Cell Neurosci 25(4):642–649
Eggert S et al (2004) The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation. J Biol Chem 279(18):18146–18156
Walsh DM et al (2003) gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins. Biochemistry 42(22):6664–6673
von Koch CS et al (1997) Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging 18(6):661–669
Heber S et al (2000) Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J Neurosci 20(21):7951–7963
Beglopoulos V et al (2004) Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. J Biol Chem 279(45):46907–46914
Shariati SA, De Strooper B (2013) Redundancy and divergence in the amyloid precursor protein family. FEBS Lett 587(13):2036–2045
Scheinfeld MH, Matsuda S, D’Adamio L (2003) JNK-interacting protein-1 promotes transcription of A beta protein precursor but not A beta precursor-like proteins, mechanistically different than Fe65. Proc Natl Acad Sci USA 100(4):1729–1734
Gersbacher MT et al (2013) Turnover of amyloid precursor protein family members determines their nuclear signaling capability. PLoS One 8(7):e69363
Lorent K et al (1995) Expression in mouse embryos and in adult mouse brain of three members of the amyloid precursor protein family, of the alpha-2-macroglobulin receptor/low density lipoprotein receptor-related protein and of its ligands apolipoprotein E, lipoprotein lipase, alpha-2-macroglobulin and the 40,000 molecular weight receptor-associated protein. Neuroscience 65(4):1009–1025
Dimitrov M et al (2013) Alzheimer’s disease mutations in APP but not gamma-secretase modulators affect epsilon-cleavage-dependent AICD production. Nat Commun 4:2246
Schettini G et al (2010) Phosphorylation of APP-CTF-AICD domains and interaction with adaptor proteins: signal transduction and/or transcriptional role–relevance for Alzheimer pathology. J Neurochem 115(6):1299–1308
Zhang C et al (2007) An AICD-based functional screen to identify APP metabolism regulators. Mol Neurodegener 2:15
Nunan J, Small DH (2002) Proteolytic processing of the amyloid-beta protein precursor of Alzheimer’s disease. Essays Biochem 38:37–49
Scheinfeld MH et al (2002) Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription. J Biol Chem 277(46):44195–44201
Muller T et al (2013) A ternary complex consisting of AICD, FE65, and TIP60 down-regulates Stathmin1. Biochim Biophys Acta 1834(1):387–394
Cao X, Sudhof TC (2001) A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293(5527):115–120
Tang X et al (2007) Amyloid-beta precursor-like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress. Oncogene 26(52):7302–7312
Mayer MC et al (2014) Novel zinc-binding site in the E2 domain regulates amyloid precursor-like protein 1 (APLP1) oligomerization. J Biol Chem 289(27):19019–19030
Bayer TA et al (1997) Amyloid precursor-like protein 1 accumulates in neuritic plaques in Alzheimer’s disease. Acta Neuropathol 94(6):519–524
McNamara MJ et al (1998) Immunohistochemical and in situ analysis of amyloid precursor-like protein-1 and amyloid precursor-like protein-2 expression in Alzheimer disease and aged control brains. Brain Res 804(1):45–51
Yanagida K et al (2009) The 28-amino acid form of an APLP1-derived Abeta-like peptide is a surrogate marker for Abeta42 production in the central nervous system. EMBO Mol Med 1(4):223–235
Portelius E et al (2014) Altered cerebrospinal fluid levels of amyloid beta and amyloid precursor-like protein 1 peptides in Down’s syndrome. Neuromol Med 16(2):510–516
Zheng H et al (1995) beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81(4):525–531
Guilarte TR et al (2008) Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. J Neurochem 105(5):1948–1959
Bergmans BA et al (2010) Neurons generated from APP/APLP1/APLP2 triple knockout embryonic stem cells behave normally in vitro and in vivo: lack of evidence for a cell autonomous role of the amyloid precursor protein in neuronal differentiation. Stem Cells 28(3):399–406
Guilarte TR (2010) APLP1, Alzheimer’s-like pathology and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. Neurotoxicology 31(5):572–574
Merdes G et al (2004) Interference of human and Drosophila APP and APP-like proteins with PNS development in Drosophila. EMBO J 23(20):4082–4095
Slack C et al (2011) dFOXO-independent effects of reduced insulin-like signaling in Drosophila. Aging Cell 10(5):735–748
Wang X et al (2014) FoxO mediates APP-induced AICD-dependent cell death. Cell Death Dis 5:e1233
Ma X et al (2013) dUev1a modulates TNF-JNK mediated tumor progression and cell death in Drosophila. Dev Biol 380(2):211–221
Igaki T, Pagliarini RA, Xu T (2006) Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr Biol 16(11):1139–1146
Xue L, Noll M (2002) Dual role of the Pax gene paired in accessory gland development of Drosophila. Development 129(2):339–346
Ma X et al (2014) Bendless modulates JNK-mediated cell death and migration in Drosophila. Cell Death Differ 21(3):407–415
Hay BA, Wolff T, Rubin GM (1994) Expression of baculovirus P35 prevents cell death in Drosophila. Development 120(8):2121–2129
Wang SL et al (1999) The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell 98(4):453–463
Lisi S, Mazzon I, White K (2000) Diverse domains of THREAD/DIAP1 are required to inhibit apoptosis induced by REAPER and HID in Drosophila. Genetics 154(2):669–678
Rosen DR et al (1989) A Drosophila gene encoding a protein resembling the human beta-amyloid protein precursor. Proc Natl Acad Sci USA 86(7):2478–2482
Martin-Morris LE, White K (1990) The Drosophila transcript encoded by the beta-amyloid protein precursor-like gene is restricted to the nervous system. Development 110(1):185–195
Torroja L et al (1999) The Drosophila beta-amyloid precursor protein homolog promotes synapse differentiation at the neuromuscular junction. J Neurosci 19(18):7793–7803
Gunawardena S, Goldstein LS (2001) Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32(3):389–401
Torroja L et al (1999) Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport. Curr Biol 9(9):489–492
Soldano A et al (2013) The Drosophila homologue of the amyloid precursor protein is a conserved modulator of Wnt PCP signaling. PLoS Biol 11(5):e1001562
Kim HJ et al (2007) Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development. Cell Death Differ 14(1):103–115
Kajihara T et al (2006) Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization. Mol Endocrinol 20(10):2444–2455
Bouchard C et al (2007) FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev 21(21):2775–2787
Luo X et al (2007) Foxo and Fos regulate the decision between cell death and survival in response to UV irradiation. EMBO J 26(2):380–390
Siegrist SE et al (2010) Inactivation of both Foxo and reaper promotes long-term adult neurogenesis in Drosophila. Curr Biol 20(7):643–648
Shen J, Tower J (2010) Drosophila foxo acts in males to cause sexual-dimorphism in tissue-specific p53 life span effects. Exp Gerontol 45(2):97–105
You H, Mak TW (2005) Crosstalk between p53 and FOXO transcription factors. Cell Cycle 4(1):37–38
Fu W et al (2009) MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. J Biol Chem 284(21):13987–14000
Acknowledgments
We thank Dr. Merders, Dr. Partridge and the Bloomington Drosophila Stock Center for fly stocks. This work is supported by the National Basic Research Program of China (973 Program) (2010CB944901, 2011CB943903), National Natural Science Foundation of China (31071294, 31171413, 31371490), the Specialized Research Fund for the Doctoral Program of Higher Education of China (20120072110023), and Shanghai Committee of Science and Technology (09DZ2260100, 14JC1406000).
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10495_2015_1097_MOESM1_ESM.docx
Fig. S1 APLP1 induces cell death and defects in wing development. Fluorescent images of GFP expression (a) or acridine orange staining (b, c) of wing discs from 3rd instar larvae and light images of adult wing (e-g) are shown. dpp-Gal4 was used as a control (b,f), or to drive the expression of GFP (a,e) or APLP1 (c, g). The lower panels are high magnification of the boxed areas in the upper panels. d shows the statistical analysis of acridine orange-positive cells in band c, whereas h shows the statistical analysis of the acv presence in f andg.***: P ≤ 0.001. Genotypes: UAS-GFP/+ ; dpp-Gal4/+ (a,e); dpp-Gal4/+ (b, f); dpp-Gal4/UAS-APLP1 (c,g) (DOCX 201 kb)
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Fig. S2 APLP1 induces cell death in the wing pouch area. Fluorescent images of GFP expression (a) or acridine orange staining (b, c) of wing discs from 3rd instar larvae are shown. sd-Gal4 was used as a control (b), or to drive the expression of GFP (a) or APLP1 (c). The lower panels are high magnification of the boxed areas in the upper panels. Genotypes: sd-Gal4/+ ; UAS-GFP/+ (a); sd-Gal4/+ (b);sd-Gal4/+ ; UAS-APLP1/+ (c) (DOCX 159 kb)
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Fig. S3 Loss of dfoxO suppresses APLP1-induced blistered wing phenotype. (a-c) Light images of adult wings are shown. Compared with the sd-Gal4 control (a), expression of APLP1 produced a blistered wing phenotype (b), which was suppressed in heterozygous dfoxO mutants (c). The red arrow indicates a blister on the wing. d is the statistical analysis of the presence of blistered wing.***, P ≤ 0.001. Genotypes: sd-Gal4/+ (a); sd-Gal4/+ ;UAS-APLP1/+ (b); sd-Gal4/+ ;UAS-APLP1/dfoxO △94 (c) (DOCX 155 kb)
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Fig.S4 APLP1 induces dFoxO-mediated cell death in the notum. Fluorescent images of acridine orange staining of notum tips of the wing discs from 3rd instar larvae are shown(a-c). Compared with the pnr-Gal4 control (a), expression of APLP1 resulted in enhanced cell death in the notum (b), which was suppressed by the expression of a dfoxO RNAi (c). The lower panels are high magnification of the boxed areas in the upper panels. d is the statistical analysis of acridine orange-positive cells in a-c.***, P ≤ 0.001; **, P ≤ 0.01. Genotypes: pnr-Gal4/+ (a); pnr-Gal4/UAS-APLP1 (b); pnr-Gal4 UAS-APLP1/UAS-dfoxO-IR#1 (c) (DOCX 118 kb)
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Fig. S5 APLP1 induces cell death in the nervous system. Fluorescent images of GFP expression (a, e) or acridine orange staining (b, c, f, g) of the ventral nervecord (VNC) or eye disc from 3rd instar larvae are shown. elav-Gal4 and GMR-Gal4 were used as controls(b, f), or to drive the expression of GFP (a, e) or APLP1 (c, g). d shows statistical analysis of AO positive cells in b and c.**, P < 0.01. h shows statistical analysis of AO positive cells in f and g.***: P ≤ 0.001. Genotypes: elav-Gal4/+ ; UAS-GFP/+ (a); elav-Gal4/+ (b);elav-Gal4/+ ; UAS-APLP1/+ (c); UAS-GFP/+ ; GMR-Gal4/+ (e); GMR-Gal4/+ (f); GMR-Gal4/UAS-APLP1 (g) (DOCX 177 kb)
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Fig. S6 APLP2 induces cell death and defects in wing development. Acridine orange staining (a, b) of wing discs from 3rd instar larvae and light images of adult wing (d,e) are shown. ptc-Gal4 was used as a control (a,d), or to drive the expression of APLP2 (b, e). The lower panels are high magnification of the boxed areas in the upper panels. c shows the statistical analysis of acridine orange-positive cells in a and b. f shows the statistical analysis of theacv presence in dande.***: P ≤ 0.001. Genotypes: ptc-Gal4/+ (a, d); ptc-Gal4/UAS-APLP2(b,e) (DOCX 275 kb)
10495_2015_1097_MOESM7_ESM.docx
Fig. S7 APLP2 induces cell death and defects in the wing and thorax. Acridine orange staining (a, b) of wing discs from 3rd instar larvae and light images of adult wing (c, d) or thorax (e, f) are shown. sd-Gal4 (a, c) or pnr-Gal4 (e) was used as controls, or to drive the expression of APLP2(b, d, f). The lower panels are high magnification of the boxed areas in the upper panels. Genotypes: sd-Gal4/+ (a, c); sd-Gal4/+ ; UAS-APLP2/+ (b, d); pnr-Gal4/+ (e); UAS-APLP2/+ ; pnr-Gal4/+ (f) (DOCX 251 kb)
10495_2015_1097_MOESM8_ESM.docx
Fig. S8 APPL induces cell death in the nervous system. Fluorescent images of RFP expression (a) or acridine orange staining (b, c) of the ventral nervecord from 3rd instar larvae are shown. APPL-Gal4 was used as a control (b), or to drive the expression of RFP (a) or APPLsd (c). The dashed white box indicates the ventral nerve cord middle line. The lower panels are high magnification of the boxed areas in the upper panels. d shows the statistical analysis of AO positive cells in b and c.**, P < 0.01. Genotypes: APPL-Gal4/+ ; UAS-RFP/+ (a); APPL-Gal4/+ (b);APPL-Gal4/+ ; UAS-APPLsd/+ (c) (DOCX 191 kb)
10495_2015_1097_MOESM9_ESM.docx
Fig. S9 Expression of FoxO proteins produces the loss-of-acv phenotype. (a-c) Light images of adult wings are shown. Compared with the ptc-Gal4 control (a), expression of dFoxO or hFoxO3a resulted in the loss-of-acv phenotype (b, c). The lower panels are high magnification of the boxed areas in the upper panels. d shows the statistical analysis of the presence of acv in a-c.***, P ≤ 0.001. Genotypes: ptc-Gal4/+ (a); ptc-Gal4/+ ;UAS-dFoxO/+ (b); ptc-Gal4/+ ;UAS-hFoxO3a/+ (c) (DOCX 220 kb)
10495_2015_1097_MOESM10_ESM.docx
Fig. S10 Expression of APLP2 activates the transcription of FoxO target genes. Light images of Drosophila 3rd instar wing discs are shown. X-Gal staining of hid-LacZ and reaper-LacZ reporters in the wing pouch (a, c) are dramatically up-regulated by the expression of APLP2 (b, d) (DOCX 190 kb)
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Wang, X., Ma, Y., Zhao, Y. et al. APLP1 promotes dFoxO-dependent cell death in Drosophila . Apoptosis 20, 778–786 (2015). https://doi.org/10.1007/s10495-015-1097-1
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DOI: https://doi.org/10.1007/s10495-015-1097-1