Abstract
Amyloid precursor protein (APP) and amyloid β-peptide (Aβ) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit α as a binding partner of the extracellular domain of APP and Aβ. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit α reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit α. The extracellular domain of APP and Aβ partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Aβ is similar in structure to the ATP synthase–binding sequence of the inhibitor of F1 (IF1), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Aβ and IF1 similarly impair both short- and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Aβ regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Aβ-mediated Alzheimer's disease pathology.
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References
Turner PR, O’Connor K, Tate WP, Abraham WC . Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 2003; 70: 1–32.
Lazarov O, Lee M, Peterson DA, Sisodia SS . Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci 2002; 22: 9785–9793.
Mita S, Schon EA, Herbert J . Widespread expression of amyloid beta-protein precursor gene in rat brain. Am J Pathol 1989; 134: 1253–1261.
Mattson MP, Chen SL . Neuronal and glial calcium signaling in Alzheimer's disease. Cell Calcium 2003; 24: 385–397.
Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ . The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem 2001; 276: 40288–40292.
Furukawa K, Barger SW, Blalock EM, Mattson MP . Activation of K+ channels and suppression of neuronal activity by secreted beta-amyloid-precursor protein. Nature 1996; 379: 74–78.
Barger SW, Mattson MP . Induction of neuroprotective κB-dependent transcription by secreted forms of the Alzheimer's beta-amyloid precursor. Brain Res Mol Brain Res 1996; 40: 116–126.
Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T et al. APP processing and synaptic function. Neuron 2003; 37: 925–937.
Caille II, Allinquant B, Dupont E, Bouillot C, Langer A, Muller U et al. Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone. Development 2004; 131: 2173–2181.
Bayer TA, Cappai R, Masters CL, Beyreuther K, Multhaup G . It all sticks together—the APP-related family of proteins and Alzheimer's disease. Mol Psychiatry 1999; 4: 524–528.
Wilquet V, De Strooper B . Amyloid-beta precursor protein processing in neurodegeneration. Curr Opin Neurobiol 2004; 14: 582–588.
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Loosatos M et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 1998; 95: 6448–6453.
Kayed R, Head E, Thompson JL, Milton SC, Cotman CW, Glabe CG . Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003; 300: 486–489.
Mattson MP . Pathways towards and away from Alzheimer's disease. Nature 2004; 430: 631–639.
Dodart JC, Mathis C, Bales KR, Paul SM . Does my mouse have Alzheimer's disease? Genes Brain Behav 2002; 1: 142–155.
Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B et al. Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol 2003; 62: 885–898.
Cabezon E, Montgomery MG, Leslie AGW, Walker JE . The structure of bovine F1-ATPase in complex with its regulatory protein IF1 . Nat Struct Biol 2003; 10: 744–750.
Vinogadov AD . Mitochondrial ATP synthase: fifteen years later. Biochemistry (Mosc) 1999; 64: 1443–1456.
Moser TL, Kenan DJ, Ashley TA, Roy JA, Goodmann MD, Misra UK et al. Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci USA 2001; 98: 6656–6661.
Arakaki N, Nagao T, Niki R, Toyofuku A, Tanaka H, Kuramato Y et al. Possible role of cell surface H+-ATP synthase in the extracellular ATP synthesis and proliferation of human umbilical vein endothelial cells. Mol Cancer Res 2003; 1: 931–939.
Bae TJ, Kim MS, Kim JW, Choo HJ, Lee JW, Kim KB et al. Lipid raft proteome reveals ATP synthase complex in the cell surface. Proteomics 2004; 4: 3536–3548.
Kim BW, Choo HJ, Lee JW, Kim JH, Ko YG . Extracellular ATP is generated by ATP synthase complex in adipocyte rafts. Exp Mol Med 2004; 36: 475–485.
Fujii S . ATP- and adenosine-mediated signaling in the central nervous system: the role of extracellular ATP in hippocampal long-term potentiation. J Pharmacol Sci 2004; 94: 103–106.
Delius JA, Kramer I, Schachner M, Singer W . NCAM 180 in the postnatal development of cat visual cortex: an immunohistochemical study. J Neurosci Res 1997; 49: 255–267.
Stalder M, Phinney A, Probst A, Sommer B, Staufenbiel M, Jucker M . Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am J Pathol 1999; 154: 1627–1631.
Chen S, Mantei N, Dong L, Schachner M . Prevention of neural cell death by neural adhesion molecules L1 and CHL1. J Neurobiol 1999; 38: 428–439.
Xu X, Yang D, Wyss-Coray T, Yan J, Gan L, Sun Y et al. Wild type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc Natl Acad Sci USA 1999; 96: 7547–7552.
Neuhoff H, Sassoe-Pognetto M, Panzanelli P, Maas C, Witke W, Kneussel M . The actin-binding protein profilin I is localized at synaptic sites in an activity-regulated manner. Eur J Neurosci 2005; 21: 15–25.
Feng B, Tabas I . ABCA1-mediated cholesterol efflux is defective in free cholesterol-loaded macrophages. Mechanism involves enhanced ABCA1 degradation in a process requiring full NPC1 activity. J Biol Chem 2002; 277: 43271–43280.
Zhao Y, Zhang W, Kho Y, Zhao Y . Proteomic analysis of integral plasma membrane proteins. Anal Chem 2004; 76: 1817–1823.
Fernández-Vizarra E, Lopez-Perez MJ, Enriquez JA . Isolation of biogenetically competent mitochondria from mammalian tissues and cultured cells. Methods 2002; 26: 292–297.
Kleene R, Classen B, Zdizieblo J, Schrader M . SH3 binding sites of ZG29p mediate an interaction with amylase and are involved in condensation-sorting in the exocrine rat pancreas. Biochemistry 2000; 39: 9893–9900.
Shevchenko A, Wilm M, Vorm O, Mann M . Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal Chem 1996; 68: 850–858.
Kleene R, Yang H, Kutsche M, Schachner M . The neural recognition molecule L1 is a sialic acid-binding lectin for CD24, which induces promotion and inhibition of neurite outgrowth. J Biol Chem 2001; 276: 21656–21663.
Moser TL, Stack MS, Asplin I, Enghild JJ, Hojrup P, Everitt L et al. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc Natl Acad Sci USA 1999; 96: 2811–2816.
Burwick NR, Wahl ML, Fang J, Zhong Z, Moser TL, Li B et al. An inhibitor of the F1 subunit of ATP synthase (IF1) modulates the activity of angiostatin on the endothelial cell surface. J Biol Chem 2005; 280: 1740–1745.
Das AM, Harris DA . Regulation of the mitochondrial ATP synthase in intact rat cardiomyocytes. Biochem J 1990; 266: 355–361.
Eckhardt M, Bukalo O, Chazal G, Wang L, Goridis C, Schachner M et al. Mice deficient in the polysialytransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity. J Neurosci 2000; 20: 5234–5244.
Evers MR, Salmen B, Bukalo O, Rollenhagen A, Bosl MR, Morellini F et al. Impairment of L-type Ca2+ channel-dependent forms of hippocampal synaptic plasticity in mice deficient in the extracellular matrix glycoprotein tenascin-C. J Neurosci 2002; 22: 7177–7194.
Wang HW, Pasternak JF, Kuo H, Ristic H, Lambert MP, Chromy B et al. Soluble oligomers of beta amyloid (1–42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res 2002; 924: 133–140.
Scheuermann S, Hambsch B, Hesse L, Stumm J, Schmidt C, Beher D et al. Homodimerization of amyloid precursor protein and its implication in the amyloidogenic pathway of Alzheimer's disease. J Biol Chem 2001; 276: 33923–33929.
Ida N, Hartmann T, Pantel J, Zerfass R, Forstl H, Sandbrink R et al. Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive western blot assay. J Biol Chem 1996; 271: 22908–22914.
Van Raaij MJ, Orriss GL, Montgomery MG, Runswick MJ, Fearnley IM, Skehel JM et al. The ATPase inhibitor protein from bovine heart mitochondria: the minimal inhibitory sequence. Biochemistry 1996; 35: 15618–15625.
Bianchet MA, Hullihen J, Pedersen PL, Amzel LM . The 2.8-Å structure of rat liver F1-ATPase: configuration of a critical intermediate in ATP synthesis/hydrolysis. Proc Natl Acad Sci USA 1998; 95: 11065–11070.
Xie CW . Calcium-regulated signaling pathways: role in amyloid beta-induced synaptic dysfunction. Neuromol Med 2004; 6: 53–64.
Cabezon E, Butler PJ, Runswick MJ, Walker JE . Modulation of the oligomerization state of the bovine F1-ATPase inhibitor protein, IF1, by pH. J Biol Chem 2000; 275: 25460–25464.
Matter ML, Zhang Z, Norstedt C, Ruoslahti E . The α5β1 integrin mediates the elimination of amyloid-β peptide and protects against apoptosis. J Cell Biol 1998; 141: 1019–1030.
Veitonmäki N, Cao R, Wu LH, Moser TL, Li B, Pizzo SV et al. Endothelial cell surface ATP synthase-triggered caspase-apoptotic pathway is essential for k1-5-induced antiangiogenesis. Cancer Res 2004; 64: 3679–3686.
Chi SL, Pizzo SV . Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase. Cancer Res 2006; 66: 875–882.
Koshida R, Jingsong O, Matsunaga T, Chilian WM, Oldham KT, Ackerman AW et al. Angiostatin: a negative regulator of endothelial-dependent vasodilation. Circulation 2003; 107: 803–806.
Paris D, Townsend K, Quadros A, Humphrey J, Sun J, Brem S et al. Inhibition of angiogenesis by Aβ peptides. Angiogenesis 2004; 7: 75–85.
Price JM, Chi X, Hellermann G, Sutton ET . Physiological levels of beta-amyloid induce cerebral vessel dysfunction and reduce endothelial nitric oxide production. Neurol Res 2001; 23: 506–512.
Moser TL, Stack MS, Wahl ML, Pizzo SV . The mechanism of action of angiostatin: can you teach an old dog new tricks? Thromb Haemost 2002; 87: 294–301.
Parkin ET, Turner AJ, Hooper NM . Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft protein. Biochem J 1999; 344: 23–30.
Kaether C, Haass C . A lipid boundary separates APP and secretases and limits amyloid beta-peptide generation. J Cell Biol 2004; 167: 809–812.
Vetrivel KS, Cheng H, Kim S-H, Chen Y, Barnes NY, Parent AT et al. Spatial segregation of γ-secretase and substrate in distinct membrane domains. J Biol Chem 2005; 280: 25892–25900.
Lovell MA, Xiong S, Markesbery WR, Lynn BC . Quantitative proteomic analysis of mitochondria from primary neuron cultures treated with amyloid beta peptide. Neurochem Res 2005; 30: 113–122.
Fai Poon H, Farr SA, Banks WA, Pierce WM, Klein JB, Morley JE et al. Proteomic identification of less oxidized brain proteins in aged senescence-accelerated mice following administration of antisense oligonucleotide directed at the Aβ region of amyloid precursor protein. Mol Brain Res 2005; 138: 8–16.
Wirths O, Multhaup G, Bayer TA . A modified beta-amyloid hypothesis: intraneuronal accumulation of the beta-amyloid peptide—the first step of a fatal cascade. J Neurochem 2004; 91: 513–529.
Reddy PH . Amyloid precursor protein-mediated free radicals and oxidative damage: implications for development and progression of Alzheimer's disease. J Neurochem 2006; 96: 1–13.
Anandatheerthavarada HK, Biswas G, Robin M-A, Avadhani NG . Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol 2003; 161: 41–54.
Hansson CA, Frykman S, Farmery MR, Tjernberg LO, Nilsberth C, Pursglove SE et al. Nicastrin, presenilin, aph-1, and pen-2 form active γ-secretase complexes in mitochondria. J Biol Chem 2004; 279: 51654–51660.
Khan SM, Cassarino DS, Abramov NN, Keeny PM, Borland MK, Trimmer PA et al. Alzheimer's disease cybrids replicate β-amyloid abnormalities through cell death pathways. Ann Neurol 2000; 48: 148–155.
Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW et al. Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J 2005; 19: 2040–2041.
Buckman JF, Reynolds IJ . Spontaneous change in mitochondrial membrane potential in cultured neurons. J Neurosci 2001; 21: 5054–5065.
Thiffault C, Bennett JP . Cyclical mitochondrial ΔΨM fluctuations linked to electron transport, F0F1 ATP-synthase and mitochondrial Na+/Ca2+ exchange are reduced in Alzheimer's disease cybrids. Mitochondrion 2005; 5: 109–119.
Walsh DM, Selkoe DJ . Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 2004; 44: 181–193.
Zimmermann H . Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 299–309.
Fields RD, Stevens B . ATP: an extracellular signaling molecule between neurons and glia. Trends Neurosci 2000; 23: 625–633.
Haughey NJ, Mattson MP . Alzheimer's amyloid b-peptide enhance ATP/gap junction-mediated calcium-wave propagation in astrocytes. Neuromol Med 2003; 3: 173–180.
Urbach V, Hélix N, Renaudon B, Harvey BJ . Cellular mechanisms for apical ATP effects on intracellular pH in human bronchial epithelium. J Physiol 2002; 543: 13–21.
Kiss L, Korn SJ . Modulation of N-type Ca2+ channels by intracellular pH in chick sensory neurons. J Neurophysiol 1999; 81: 1839–1847.
Velisek L . Extracellular acidosis and high levels of carbon dioxide suppress synaptic transmission and prevent the induction of long-term potentiation in the CA1 region of rat hippocampal slices. Hippocampus 1998; 8: 24–32.
Shimokawa N, Qiu CH, Seki T, Dikic I, Koibuchi N . Phosphorylation of JNK is involved in regulation of H(+)-induced c-Jun expression. Cell Signal 2004; 16: 723–729.
Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R . Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J Neurosci 2004; 24: 3370–3378.
DeVries SH . Exocytosed protons feedback to suppress the Ca2+ current in mammalian cone photoreceptors. Neuron 2001; 32: 1107–1117.
Acknowledgements
We thank Frank Plöger and Henrike Neuhoff for preliminary experiments, Fritz Buck for sequencing of protein bands, Matthias Staufenbiel for APP transgenic mice, Gerd Multhaup for the 22C11, WO-2 and 22734 antibodies, Sangram Sisodia for mouse APP 695 cDNA, Saskia Siegel and Galina Dityateva for help with hippocampal cultures and Wiebke Höppner and Sina Müthing for help with the ATPase assay. MS is New Jersey professor for spinal cord research.
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Schmidt, C., Lepsverdize, E., Chi, S. et al. Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells. Mol Psychiatry 13, 953–969 (2008). https://doi.org/10.1038/sj.mp.4002077
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