Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides

Human Molecular Genetics

Volumn 17, Issue 22, 2008, Pages 3474-3486

  Stokin, Gorazd B ^a,d,e   Almenar Queralt, Angels ^a   Gunawardena, Shermali ^a   Rodrigues, Elizabeth M ^a   Falzone, Tomás ^a   Kim, Jungsu ^c   Lillo, Concepción ^b   Mount, Stephanie L ^a   Roberts, Elizabeth A ^a   McGowan, Eileen ^c   Williams, David S ^b   Goldstein, Lawrence S B ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b San Diego   (United States)

^c MAYO GRADUATE SCHOOL   (United States)

^d UNIVERSITY MEDICAL CENTRE LJUBLJANA   (Slovenia)

^e UNIVERSITY PSYCHIATRIC HOSPITAL   (Slovenia)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; MUTANT PROTEIN; PRESENILIN 1;

ALZHEIMER DISEASE; ANIMAL EXPERIMENT; ANIMAL TISSUE; APOPTOSIS; ARTICLE; BEHAVIOR DISORDER; CONTROLLED STUDY; DROSOPHILA; FAMILIAL DISEASE; GENE MUTATION; GENE OVEREXPRESSION; MOUSE; NERVE FIBER TRANSPORT; NEUROPATHY; NEUROTOXICITY; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; TRANSGENE;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN; AMYLOID BETA-PROTEIN PRECURSOR; ANALYSIS OF VARIANCE; ANIMALS; AXONAL TRANSPORT; AXONS; BEHAVIOR, ANIMAL; CEREBRUM; DROSOPHILA; FEAR; FEMALE; HUMANS; IMMUNOHISTOCHEMISTRY; IN SITU NICK-END LABELING; MALE; MICE; MICE, TRANSGENIC; MICROSCOPY, ELECTRON; PRESENILINS; TRANSGENES;

MUS; MUS MUSCULUS;

EID: 54949151536     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddn240     Document Type: Article

References (84)

1. Katzman, R. (1986) Alzheimer's disease. N. Engl. J. Med., 314 964-973.
2. Davies, P. and Maloney, A.J. (1976) Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet, 2, 1403.
3. Hyman, B.T., Van Horsen, G.W., Damasio, A.R. and Barnes, C.L. (1984) Alzheimer's disease: Cell-specific pathology isolates the hippocampal formation. Science, 225, 1168-1170.
4. Perry, E.K., Perry, R.H., Blessed, G. and Tomlinson, B.E. (1977) Necropsy evidence of central cholinergic deficits in senile dementia. Lancet, 1, 189.
5. Samuel, W., Terry, R.D., DeTeresa, R., Butters, N. and Masliah, E. (1994) Clinical correlates of cortical and nucleus basalis pathology in Alzheimer dementia. Arch. Neurol., 51, 772-778.
6. Meyer-Luehmann, M., Spires-Jones, T.L., Prada, C., Garcia-Alloza, M., de Calignon, A., Rozkalne, A., Koenigsknecht-Talboo, J., Holtzman, D.M., Bacskai, B.J. and Hyman, B.T. (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature, 451, 720-724.
7. Stokin, G.B., Lillo, C., Falzone, T.L., Brusch, R.G., Rockenstein, E., Mount, S.L., Raman, R., Davies, P., Masliah, E., Williams, D.S. et al. (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science, 307, 1282-1288.
8. Salehi, A., Delcroix, J.D., Belichenko, P.V., Zhan, K., Wu, C., Valletta, J.S., Takimoto-Kimura, R., Kleschevnikov, A.M., Sambamurti, K., Chung, P.P. et al. (2006) Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron, 51, 29-42.
9. Lampert, P. (1971) Fine structural changes of neurites in Alzheimer's disease. Acta. Neuropathol. (Berl.), 5 (Suppl. 5), 49-53.
10. Price, D.L., Altschuler, R.J., Struble, R.G., Casanova, M.F., Cork, L.C. and Murphy, D.B. (1986) Sequestration of tubulin in neurons in Alzheimer's disease. Brain. Res., 385, 305-310.
11. Rasool, C.G., Svendsen, C.N. and Selkoe, D.J. (1986) Neurofibrillary degeneration of cholinergic and noncholinergic neurons of the basal forebrain in Alzheimer's disease. Ann. Neurol., 20, 482-488.
12. Terry, R.D. (1963) The fine structure of neurofibrillary tangles in Alzheimer's disease. J. Neuropathol. Exp. Neurol., 22, 629-641.
13. Smith, K.D., Kallhoff, V., Zheng, H. and Pautler, R.G. (2007) In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease. Neuroimage, 35, 1401-1408.
14. Minoshima, S. and Cross, D. (2008) In vivo imaging of axonal transport using MRI: Aging and Alzheimer's disease. Eur. J. Nucl. Med. Mol. Imaging, 35 (Suppl. 1), S89-S92.
15. Stokin, G.B. and Goldstein, L.S. (2006) Linking molecular motors to Alzheimer's disease. J. Physiol. Paris, 99, 193-200.
16. Stokin, G.B. and Goldstein, L.S. (2006) Axonal transport and Alzheimer's disease. Annu. Rev. Biochem., 75, 607-627.
17. Terry, R.D. (1996) The pathogenesis of Alzheimer disease: An alternative to the amyloid hypothesis. J. Neuropathol. Exp. Neurol., 55, 1023-1025.
18. Masliah, E., Mallory, M., Deerinck, T., DeTeresa, R., Lamont, S., Miller, A., Terry, R.D., Carragher, B. and Ellisman, M. (1993) Re-evaluation of the structural organization of neuritic plaques in Alzheimer's disease. J. Neuropathol. Exp. Neurol., 52, 619-632.
19. Dickson, T.C., King, C.E., McCormack, G.H. and Vickers, J.C. (1999) Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's disease. Exp. Neurol., 156, 100-110.
20. Cork, L.C., Masters, C., Beyreuther, K. and Price, D.L. (1990) Development of senile plaques. Relationships of neuronal abnormalities and amyloid deposits. Am. J. Pathol., 137, 1383-1392.
21. Dickson, D.W., Farlo, J., Davies, P., Crystal, H., Fuld, P. and Yen, S.H. (1988) Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques. Am. J. Pathol., 132, 86-101.
22. Masliah, E., Mallory, M., Hansen, L., Alford, M., DeTeresa, R. and Terry, R. (1993) An antibody against phosphorylated neurofilaments identifies a subset of damaged association axons in Alzheimer's disease. Am. J. Pathol., 142, 871-882.
23. Chen, X.H., Johnson, V.E., Uryu, K., Trojanowski, J.Q. and Smith, D.H. (2008) A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury. Brain Pathol., Epub ahead of print.
24. Burger, P.C. and Vogel, F.S. (1973) The development of the pathologic changes of Alzheimer's disease and senile dementia in patients with Down's syndrome. Am. J. Pathol., 73, 457-476.
25. Cabrejo, L., Guyant-Marechal, L., Laquerriere, A., Vercelletto, M., De la Fourniere, F., Thomas-Anterion, C., Vemy, C., Letournel, F., Pasquier, F., Vital, A. et al. (2006) Phenotype associated with APP duplication in five families. Brain, 129, 2966-2976.
26. Rovelet-Lecrux, A., Hannequin, D., Raux, G., Le Meur, N., Laquerriere, A., Vital, A., Dumanchin, C., Feuillette, S., Brice, A., Vercelletto, M. et al. (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet., 38, 24-26.
27. Sleegers, K., Brouwers, N., Gijselinck, I., Theuns, J., Goossens, D., Wauters, J., Del-Favero, J., Cruts, M., van Duijn, C.M. and Van Broeckhoven, C. (2006) APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain 129, 2977-2983.
28. Oyama, F., Cairns, N.J., Shimada, H., Oyama, R., Titani, K. and Ihara, Y. (1994) Down's syndrome: Up-regulation of beta-amyloid protein precursor and tau mRNAs and their defective coordination. J. Neurochem., 62, 1062-1066.
29. Gunawardena, S. and Goldstein, L.S. (2001) Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron, 32, 389-401.
30. Torroja, L., Chu, H., Kotovsky, I. and White, K. (1999) Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport. Curr. Biol., 9, 489-492.
31. Brown, M.S., Ye, J., Rawson, R.B. and Goldstein, J.L. (2000) Regulated intramembrane proteolysis: A control mechanism conserved from bacteria to humans. Cell, 100, 391-398.
32. De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., Von Figura, K. and Van Leuven, F. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature, 391, 387-390.
33. De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J.S., Schroeter, E.H., Schrijvers, V., Wolfe, M.S., Ray, W.J. et al. (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature, 398, 518-522.
34. Struhl, G. and Greenwald, I. (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature, 398, 522-525.
35. Ye, Y., Lukinova, N. and Fortini, M.E. (1999) Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature, 398, 525-529.
36. Naruse, S., Thinakaran, G., Luo, J.J., Kusiak, J.W., Tomita, T., Iwatsubo, T., Qian, X., Ginty, D.D., Price, D.L., Borchelt, D.R. et al. (1998) Effects of PSI deficiency on membrane protein trafficking in neurons. Neuron, 21, 1213-1221.
37. Nishimura, M., Yu, G., Levesque, G., Zhang, D.M., Ruel, L., Chen, F., Milman, P., Holmes, E., Liang, Y., Kawarai, T. et al. (1999) Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of beta-catenin, a component of the presenilin protein complex. Nat. Med., 5, 164-169.
38. Kamal, A., Stokin, G.B., Yang, Z., Xia, C.H. and Goldstein, L.S. (2000) Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron, 28, 449-459.
39. Kamal, A., Almenar-Queralt, A., LeBlanc, J.F., Roberts, E.A. and Goldstein, L.S. (2001) Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature, 414, 643-648.
40. Lazarov, O.,Morfini, G.A., Pigino, G., Gadadhar, A., Chen, X., Robinson, J., Ho, H., Brady, S.T. and Sisodia, S.S. (2007) Impairments in fast axonal transport and motor neuron deficits in transgenic mice expressing familial Alzheimer's disease-linked mutant presenilin 1. J. Neurosci. 27, 7011-7020.
41. Pigino, G., Morfini, G., Pelsman, A., Mattson, M.P., Brady, S.T. and Busciglio, J. (2003) Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. J. Neurosci., 23, 4499-4508.
42. Cash, A.D., Aliev, G., Siedlak, S.L., Nunomura, A., Fujioka, H., Zhu, X., Raina, A.K., Vinters, H.V., Tabaton, M., Johnson, A.B. et al. (2003) Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation. Am. J. Pathol., 162, 1623-1627.
43. Terry, R.D., Gonatas, N.K. and Weiss, M. (1964) Ultrastructural studies in Alzheimer's presenile dementia. Am. J. Pathol., 44, 269-287.
44. Kim, J., Onstead, L., Randle, S., Price, R., Smithson, L., Zwizinski, C., Dickson, D.W., Golde, T. and McGowan, E. (2007) Abeta40 inhibits amyloid deposition in vivo. J. Neurosci., 27, 627-633.
45. McGowan, E., Pickford, F., Kim, J., Onstead, L., Eriksen, J., Yu, C., Skipper, L., Murphy, M.P., Beard, J., Das, P. et al. (2005) Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron, 47, 191-199.
46. Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G. and Ghiso, J. (1999) A stop-codon mutation in the BRI gene associated with familial British dementia. Nature, 399, 776-781.
47. Vidal, R., Revesz, T., Rostagno, A., Kim, E., Holton, J.L., Bek, T., Bojsen-Moller, M., Braendgaard, H., Plant, G., Ghiso, J. et al. (2000) A decamer duplication in the 3′ region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proc. Natl Acad. Sci. USA, 97, 4920-4925.
48. Bernstein, M. and Lichtman, J.W. (1999) Axonal atrophy: The retraction reaction. Curr. Opin. Neurobiol., 9, 364-370.
49. Gunawardena, S., Her, L.S., Brusch, R.G., Laymon, R.A., Niesman, I.R., Gordesky-Gold, B., Sintasath, L., Bonini, N.M. and Goldstein, L.S. (2003) Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron, 40, 25-40.
50. Hurd, D.D. and Saxton, W.M. (1996) Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila. Genetics, 144, 1075-1085.
51. Lampert, P.W. (1967) A comparative electron microscopic study of reactive, degenerating, regenerating and dystrophic axons. J. Neuropathol. Exp. Neurol., 26, 345-368.
52. Wong, T.P., Debeir, T., Duff, K. and Cuello, A.C. (1999) Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1 and amyloid precursor protein transgenes. J. Neurosci., 19, 2706-2716.
53. Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F. and Cole, G. (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science, 274 99-102.
54. Fossella, J., Samant, S.A., Silver, L.M., King, S.M., Vaughan, K.T., Olds-Clarke, P., Johnson, K.A., Mikami, A., Vallee, R.B. and Pilder, S.H. (2000) An axonemal dynein at the Hybrid Sterility 6 locus: implications for t haplotype-specific male sterility and the evolution of species barriers. Mamm. Genome, 11, 8-15.
55. Ye, Y. and Fortini, M.E. (1999) Apoptotic activities of wild-type and Alzheimer's disease-related mutant presenilins in Drosophila melanogaster. J. Cell Biol., 146, 1351-1364.
56. Dineley, K.T., Xia, X., Bui, D., Sweatt, J.D. and Zheng, H. (2002) Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins. J. Biol. Chem., 277, 22768-22780.
57. Holcomb, L., Gordon, M.N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D. et al. (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med., 4, 97-100.
58. Holcomb, L.A., Gordon, M.N., Jantzen, P., Hsiao, K., Duff, K. and Morgan, D. (1999) Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: Lack of association with amyloid deposits. Behav. Genet., 29, 177-185.
59. Cai, D., Leem, J.Y., Greenfield, J.P., Wang, P., Kim, B.S., Wang, R., Lopes, K.O., Kim, S.H., Zheng, H., Greengard, P. et al. (2003) Presenilin-1 regulates intracellular trafficking and cell surface delivery of beta-amyloid precursor protein. J. Biol. Chem., 278 3446-3454.
60. Rusu, P., Jansen, A., Soba, P., Kirsch, J., Lower, A., Merdes, G., Kuan, Y.H., Jung, A., Beyreuther, K., Kjaerulff, O. et al. (2007) Axonal accumulation of synaptic markers in APP transgenic Drosophila depends on the NPTY motif and is paralleled by defects in synaptic plasticity, Eur. J. Neurosci., 25, 1079-1086.
61. Cavalli, V., Kujala, P., Klumperman, J. and Goldstein, L.S. (2005) Sunday Driver links axonal transport to damage signaling. J. Cell Biol., 168, 775-787.
62. Hernandez, D., Sugaya, K., Qu, T., McGowan, E., Duff, K. and McKinney, M. (2001) Survival and plasticity of basal forebrain cholinergic systems in mice transgenic for presenilin-1 and amyloid precursor protein mutant genes. Neuroreport, 12, 1377-1384.
63. Galvan, V., Gorostiza, O.F., Banwait, S., Ataie, M., Logvinova, A.V., Sitaraman, S., Carlson, E., Sagi, S.A., Chevallier, N., Jin, K. et al. (2006) Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc. Natl Acad. Sci. USA, 103, 7130-7135.
64. Kaether, C., Lammich, S., Edbauer, D., Ertl, M., Rietdorf, J., Capell, A., Steiner, H. and Haass, C. (2002) Presenilin-1 affects trafficking and processing of betaAPP and is targeted in a complex with nicastrin to the plasma membrane. J. Cell Biol., 158, 551-561.
65. Kim, S.H., Leem, J.Y., Lah, J.J., Slunt, H.H., Levey, A.I., Thinakaran, G. and Sisodia, S.S. (2001) Multiple effects of aspartate mutant presenilin 1 on the processing and trafficking of amyloid precursor protein. J. Biol. Chem., 276, 43343-43350.
66. Leem, J.Y., Saura, C.A., Pietrzik, C., Christianson, J., Wanamaker, C., King, L.T., Veselits, M.L., Tomita, T., Gasparini, L., Iwatsubo, T. et al. (2002) A role for presenilin 1 in regulating the delivery of amyloid precursor protein to the cell surface. Neurobiol. Dis., 11, 64-82.
67. Cai, D., Zhong, M., Wang, R., Netzer, W.J., Shields, D., Zheng, H., Sisodia, S.S., Foster, D.A., Gorelick, F.S., Xu, H. et al. (2006) Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons. Proc. Natl Acad. Sci. USA, 103, 1936-1940.
68. Lee, E.B., Zhang, B., Liu, K., Greenbaum, E.A., Doms, R.W., Trojanowski, J.Q. and Lee, V.M. (2005) BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo. J. Cell Biol., 168, 291-302.
69. Yu, H., Saura, C.A., Choi, S.Y., Sun, L.D., Yang, X., Handler, M., Kawarabayashi, T., Younkin, L., Fedeles, B., Wilson, M.A. et al. (2001) APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron, 31, 713-726.
70. Tezapsidis, N., Merz, P.A., Merz, G. and Hong, H. (2003) Microtubular interactions of presenilin direct kinesis of Abeta peptide and its precursors. FASEB J., 17, 1322-1324.
71. Borchelt, D.R., Thinakaran, G., Eckman, C.B., Lee, M.K., Davenport, F., Ratovitsky, T., Prada, C.M., Kim, G., Seekins, S., Yager, D. et al. (1996) Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1- 42/1-40 ratio in vitro and in vivo. Neuron, 17 1005-1013.
72. Borchelt, D.R., Ratovitski, T., van Lare, J., Lee, M.K., Gonzales, V., Jenkins, N.A., Copeland, N.G., Price, D.L. and Sisodia, S.S. (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron, 19, 939-945.
73. Fossgreen, A., Bruckner, B., Czech, C., Masters, C.L., Beyreuther, K. and Paro, R. (1998) Transgenic Drosophila expressing human amyloid precursor protein show gamma-secretase activity and a blistered-wing phenotype. Proc. Natl Acad. Sci. USA, 95, 13703-13708.
74. Ye, Y. and Fortini, M.E. (2000) Proteolysis and developmental signal transduction. Semin. Cell Dev. Biol., 11, 211-221.
75. Gundersen, H.J. (1986) Stereology of arbitrary particles. A review of unbiased number and size estimators and the presentation of some new ones, in memory of William R. Thompson. J. Microsc, 143, 3-45.
76. West, M.J., Slomianka, L. and Gundersen, H.J. (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat. Rec., 231, 482-497.
77. Jensen, E.B. and Gundersen, H.J. (1993) The rotator. J. Microsc., 170, 35-44.
78. Geula, C. and Mesulam, M.M. (1996) Systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer's disease. Cereb. Cortex, 6, 165-177.
79. Geula, C. and Mesulam, M.M. (1989) Cortical cholinergic fibers in aging and Alzheimer's disease: A morphometric study. Neuroscience, 33 469-481.
80. Xia, C., Rahman, A., Yang, Z. and Goldstein, L.S. (1998) Chromosomal localization reveals three kinesin heavy chain genes in mouse. Genomics, 52, 209-213.
81. Bowman, A.B., Kamal, A., Ritchings, B.W., Philp, A.V., McGrail, M., Gindhart, J.G. and Goldstein, L.S. (2000) Kinesin-dependent axonal transport is mediated by the Sunday driver (SYD) protein. Cell, 103, 583-594.
82. Kawarabayashi, T., Younkin, L.H., Saido, T.C., Shoji, M., Ashe, K.H. and Younkin, S.G. (2001) Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J. Neurosci., 21, 372-381.
83. Hsiao, K.K., Borchelt, D.R., Olson,K., Johannsdottir, R., Kitt, C., Yunis,W., Xu, S., Eckman, C., Younkin, S., Price, D. et al. (1995) Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron, 15 1203-1218.
84. Limback-Stokin, K., Korzus, E., Nagaoka-Yasuda, R. and Mayford, M. (2004) Nuclear calcium/calmodulin regulates memory consolidation. J. Neurosci., 24, 10858-10867.