Summary
Animal models provide unique opportunities to analyze mechanisms of βamyloid protein (Aβ) amyloidogenesis. One set of studies in control animals was designed to identify the neural cells that express the amyloid precursor protein (APP) and to characterize the transport and processing of APP in vivo. APP is synthesized by neurons and transported by fast axonal transport to terminals, where it may play a role in cell-cell and synaptic interactions. A second group of investigations focused on amyloidogenesis in aged nonhuman primates. In late middle life, monkeys develop age-associated impairments in performance on cognitive/memory tasks and begin to show brain abnormalities, including deposits of Aβ and formation of neurites. Amyloid is readily demonstrable in proximity to APP-enriched swollen axonal terminals and dendrites, suggesting that neurons may be one source of Aβ. However, in ways not yet clear, astrocytes, microglia, and vascular cells may also contribute to the formation of Aβ. In the neuropil of brain, alterations in the normal biology of APP may lead not only to the formation of amyloid fibrils but may also impair synaptic interactions, resulting in synaptic disjunction and disconnection. More recently, in a third set of experiments, we have begun to examine transgenic mice, generated by the yeast artificial chromosome (YAC)-embryonic stem (ES) cell technique. These animals express the entire human APP gene and transgene expression that approximates levels of endogenous APP. These mice, trisomic for APP, may develop Alzheimer’s disease (AD)-type pathology, as occurs in individuals with Down’s syndrome (trisomy 21). Finally, recent research is designed to produce transgenic mice with AD-linked APP mutations; these studies are essential for determining some of the genetic/molecular/biochemical mechanisms that cause AD-type brain lesions in familial AD (FAD). The strategies that have proved valuable in aged monkeys will be very helpful in studies of these mice. Both nonhuman primate and transgenic models will permit the testing of therapeutic approaches designed to ameliorate some of the abnormalities that occur in humans with AD. In conclusion, this review summarizes briefly the features of AD relevant to these studies and outlines some of our research focusing on the biology of APP in neural tissues and animal models, including aged nonhuman primates and transgenic mice.
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References
Abraham CR, Selkoe DJ, Potter H, Price DL, Cork LC (1989) α1-antichymotrypsin is present together with the β-protein in monkey brain amyloid deposits. Neuroscience 32: 715–720
Anderson JP, Esch FS, Keim PS, Sambamurti K, Lieberburg I, Robakis NK (1991) Exact cleavage site of Alzheimer amyloid precursor in neuronal PC-12 cells. Neurosci Lett 128: 126–128
Arnold SE, Hyman BT, Flory, J. Damasio AR, Van Hoesen GW (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1: 103–116
Bachevalier J, Landis LS, Walker LC, Brickson M, Mishkin M, Price DL, Cork LC (1991) Aged monkeys exhibit behavioral deficits indicative of widespread cerebral dysfunction. Neurobiol Aging 12:99–111
Ball MJ, Nuttal K (1980) Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down syndrome: quantitative comparison with Alzheimer dementia. Ann Neurol 7: 462–465
Bartus RT, Fleming D, Johnson HR (1978) Aging in the rhesus monkey: debilitating effects on short-term memory. J Gerontol 33: 858–871
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82: 239–259
Brion J-P (1990) Molecular pathology of Alzheimer amyloid and neurofibrillary tangles. Sem Neurosci 2:89–100
Burger PC, Vogel FS (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
Busciglio J, Gabuzda DH, Matsudaira P, Yankner BA (1993) Generation of β-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci USA 90: 2092–2096
Cai X-D, Golde TE, Younkin SG (1993) Release of excess amyloid β protein from a mutant amyloid β protein precursor. Science 259: 514–516
Castaño EM, Ghiso J, Prelli F, Gorevic PD, Migheli A, Frangione B (1986) In vitro formation of amyloid fibrils from two synthetic peptides of different lengths homologous to Alzheimer’s disease β-protein. Biochem Biophys Res Commun 141: 782–789
Chartier-Harlin M-C, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, Mullan M (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353: 844–846
Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg, I, Selkoe DJ (1992) Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature 360: 672–674
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apoliprotein-E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261: 921–923
Cork LC, Masters C, Beyreuther K, Price DL (1990) Development of senile plaques. Relationships of neuronal abnormalities and amyloid deposits. Am J Pathol 137: 1383–1392
Crowther RA, Olesen OF, Jakes R, Goedert M (1992) The microtubule binding repeats of tau protein assemble into filaments like those found in Alzheimer’s disease, FEBS Lett. 309:199–202
Davis RT (1985) The effects of aging on the behavior of rhesus monkeys. In: Davis RT, Leathers CW (eds) Behavior and pathology of aging in rhesus monkeys. Monographs in Primatology, Vol. 8. New York, Alan R. Liss, pp 57–82
DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27: 457–463
Delaére P, He Y, Fayet G, Duyckaerts C, Hauw J-J (1993) βA4 deposits are constant in the brain of the oldest old: an immunocytochemical study of 20 French centenarians. Neurobiol Aging 14:191–194
Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdor T, McClure D, Ward PJ (1990) Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248:1122–1124
Evans DA, Funkenstein HH, Albert MS, Scherr PA, Cook NR, Chown MJ, Hebert LE, Hennekens CH, Taylor JO (1989) Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA 262:2551–2556
Fraser PE, Nguyen JT, Inouye H, Surewicz WK, Selkoe DJ, Podlisny MB, Kirschner DA (1992) Fibril formation by primate, rodent, and Dutch-hemorrhagic analogues of Alzheimer amyloid β-protein. Biochemistry 31: 10716–10723
Ghiso J, Matsubara E, Koudinov A, Choi-Miura NH, Tomita M, Wisniewski T, Frangione B (1993) The cerebrospinal-fluid soluble form of Alzheimer’s amyloid beta is complexed to SP-40, 40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex. Biochem J 293:27–30
Giaccone G, Tagliavini F, Linoli G, Bouras C, Frigerio L, Frangione B, Bugiani O (1989) Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques. Neurosci Lett 97: 232–238
Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120: 885–890
Goate A, Chartier-Harlin M-C, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349: 704–706
Goedert M, Sisodia SS, Price DL (1991) Neurofibrillary tangles and β-amyloid deposits in Alzheimer’s disease. Curr Opin Neurobiol 1: 441–447
Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8: 159–168
Golde TE, Estus S, Usiak M, Younkin LH, Younkin SG (1990) Expression of β amyloid protein precursor mRNAs: recognition of novel alternatively spliced form and quantitation in Alzheimer’s disease using PCR. Neuron 4: 253–267
Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255: 728–730
Gorevic PD, Castano EM, Sarma R, Frangione B (1987) Ten to fourteen residue peptides of Alzheimer’s disease protein are sufficient for amyloid fibril formation and its characteristic X ray diffraction pattern. Biochem Biophys Res Commun 147: 854–862
Greenberg SG, Davies P (1990) A preparation of Alzheimer paired helical filaments that displays distinct τ proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci USA 87: 5827–5831
Griffin JW, Price DL, Drachman DB, Morris J (1981) Incorporation of axonally transported glycoproteins into axolemma during nerve regeneration. J Cell Biol 88: 205–214
Grundke-Iqbal I, Iqbal K, Quinlan M, Tung Y-C, Zaidi MS, Wisniewski HM (1986) Microtubuleassociated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261: 6084–6089
Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ (1992a) Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357: 500–503
Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, Selkoe DJ (1992b) Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359: 322–325
Jarrett JT, Lansbury PT Jr (1993) Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 73: 1055–1058
Jarrett JT, Berger EP, Lansbury PT Jr (1993) The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32: 4693–4697
Johnson SA, Lampert-Etchells M, Pasinetti GM, Rozovsky I, Finch CE (1992) Complement mRNA in the mammalian brain: responses to Alzheimer’s disease and experimental brain lesioning. Neurobiol Aging 13: 641–648
Kang J, Lemaire H-G, Unterbeck A, Salbaum JM, Masters CL, Grzeschik K-H, Multhaup G, Beyreuther K, Müller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325: 733–736
Kemper T (1984) Neuroanatomical and neuropathological changes in normal aging and in dementia. In: Albert ML (ed) Clinical neurology of aging. New York, Oxford University Press, pp 9–52
Kitaguchi N, Takahashi Y, Tokushima Y, Shiojiri S, Ito H (1988) Novel precursor of Alzheimer’s disease amyloid protein shows protease inhibitory activity. Nature 331: 530–532
Kitt CA, Price DL, Struble RG, Cork LC, Wainer BH, Becher MW, Mobley WC (1984) Evidence for cholinergic neurites in senile plaques. Science 226: 1443–1445
Kitt CA, Struble RG, Cork LC, Mobley WC, Walker LC, Joh TH, Price DL (1985) Catecholaminergic neurites in senile plaques in prefrontal cortex of aged nonhuman primates. Neuroscience 16: 691–699
Koo EH, Sisodia SS, Cork LC, Unterbeck A, Bayney RM, Price DL (1990a) Differential expression of amyloid precursor protein mRNAs in cases of Alzheimer’s disease and in aged nonhuman primates. Neuron 2: 97–104
Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL (1990b) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA 87: 1561–1565
Koo EH, Abraham CR, Potter H, Cork LC, Price DL (1991) Developmental expression of α1-antichymotrypsin in brain may be related to astrogliosis. Neurobiol Aging 12:495–501
Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, Kearns WG, Pearson PL, Price DL, Gearhart JD (1993) Introduction and expression of the 400 kb precursor amyloid protein gene in transgenic mice. Nature Genetics 5: 22–30
Lee VM-Y, Balin BJ, Otvos L Jr, Trojanowski JQ (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal tau. Science 251: 675–678
Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GTAM, Luyendijk W, Frangione B (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248: 1124–1126
Mahley RW (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240: 622–630
Mann DMA, Esiri MM (1989) The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s syndrome. J Neurol Sci 89: 169–179
Martin LJ, Sisodia SS, Koo EH, Cork LC, Dellovade TL, Weidemann A, Beyreuther K, Masters C, Price DL (1991) Amyloid precursor protein in aged nonhuman primates. Proc Natl Acad Sci USA 88: 1461–1465
Masliah E, Hansen L, Albright T, Mallory M, Terry RD (1991) Immunoelectron microscopic study of synaptic pathology in Alzheimer’s disease. Acta Neuropathol 81: 428–433
Masters CL, Multhaup G, Simms G, Pottgiesser J, Martins RN, Beyreuther K (1985a) Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer’s disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J 4: 2757–2763
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985b) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82: 4245–4249
McGeer PL, Akiyama H, Itagaki S, McGeer EG (1989) Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett 107: 341–346
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34: 939–944
Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Nature Genetics 1: 345–347
Murrell J, Farlow M, Ghetti B, Benson MD (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 254: 97–99
Neve RL, Finch EA, Dawes LR (1988) Expression of the Alzheimer amyloid precursor gene transcripts in the human brain. Neuron 1: 669–677
Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Okamoto T, Murayama S, Ogata E (1993) Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G0. Nature 362:75–79
Ponte P, Gonzalez-DeWhitt P, Schilling J, Miller J, Hsu D, Greenberg B, Davis K, Wallace W, Lieberburg I, Fuller F, Cordell B (1988) A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature 331: 525–532
Presty SK, Bachevalier J, Walker LC, Struble RG, Price DL, Mishkin M, Cork LC (1987) Age differences in recognition memory of the rhesus monkey (Macaca mulatta). Neurobiol Aging 8: 435–440
Price DL, Sisodia SS. Cellular and molecular biology of Alzheimer’s diesase and animal models. Annu Rev Med, in press
Price DL, Martin LJ, Sisodia SS, Walker LC, Voytko ML, Wagster MV, Cork LC, Koliatsos VE: The aged nonhuman primate. A model for the behavioral and brain abnormalities occurring in aged human. In: Terry RD, Katzman R, and Bick KL (eds) Alzheimer disease. New York, Raven Press, in press
Probst A, Langui D, Ipsen S, Robakis N, Ulrich J (1991) Deposition of β/A4 protein along neuronal plasma membranes in diffuse senile plaques. Acta Neuropathol 83: 21–29
Quon D, Wang Y, Catalano R, Scardina JM, Murakami K, Cordell B (1991) Formation of β-amyloid protein deposits in brains of transgenic mice. Nature 352: 239–241
Rumble B, Retallack R, Hibich C, Simms G, Multhaup G, Martins R, Hockey A, Montgomery P, Beyreuther K, Masters CL (1989) Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s disease. N Engl J Med 320: 1446–1452
Saunders AM, Strittmatter WJ, Schmechel D, St George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD (1993) Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43: 1467–1472
Schubert D (1991) The possible role of adhesion in synaptic modification. Trends Neurosci 14:127–130
Selkoe DJ, Bell DS, Podlisny MB, Price DL, Cork LC (1987) Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer’s disease. Science 235: 873–877
Seubert P, Oltersdorf T, Lee MG, Barbour R, Blomquist C, Davis DL, Bryant K, Fritz LC, Galasko D, Thal LJ, Lieberburg I, Schenk DB (1993) Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide. Nature 361: 260–263
Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai X-D, McKay DM, Tintner R, Frangione B, Younkin S (1992) Production of the Alzheimer amyloid β protein by normal proteolytic processing. Science 258: 126–129
Sisodia SS (1992) β-amyloid precursor protein cleavage by a membrane-bound protease. Proc Natl Acad Sci USA 89:6075–6079
Sisodia SS, Price DL (1992) Amyloidogenesis in Alzheimer’s disease: basic biology and animal models. Curr Opin Neurobiol 2: 648–652
Sisodia SS, Koo EH, Beyreuther K, Unterbeck A, Price DL (1990) Evidence that β-amyloid protein in Alzheimer’s disease is not derived by normal processing. Science 248: 492–495
Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL (1993) Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. J Neurosci 13: 3136–3142
Slunt HH, Thinakaran G, Von Koch C, Lo ACY, Tanzi RE, Sisodia SS (1994) Expression of a ubiquitous, cross-reactive homologue of the mouse β-amyloid precursor protein (APP). J Biol Chem 269: 2637–2644
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90: 1977–1981
Struble RG, Cork LC, Whitehouse PJ, Price DL (1982) Cholinergic innervation in neuritic plaques. Science 216: 413–415
Struble RG, Price DL Jr, Cork LC, Price DL (1985) Senile plaques in cortex of aged normal monkeys. Brain Res 361: 267–275
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30: 572–580
Van Broeckhoven C, Hann J, Bakker E, Hardy JA, Van Hul W, Wehnert A, Vegter-Van der Vlis M, Roos RAC (1990) Amyloid β protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science 248 1120–1126
Walker LC, Kitt CA, Cork LC, Struble RG, Dellovade TL, Price DL (1988) Multiple transmitter systems contribute neurites to individual senile plaques. J Neuropathol Exp Neurol 47: 138–144
Walker LC, Kitt CA, Schwam E, Buckwald B, Garcia F, Sepinwall J, Price DL (1987) Senile plaques in aged squirrel monkeys. Neurobiol Aging 8: 291–296
Walker LC, Masters C, Beyreuther K, Price DL (1990) Amyloid in the brains of aged squirrel monkeys. Acta Neuropathol 80: 381–387
Wang R, Meschia JF, Cotter RJ, Sisodia SS (1991) Secretion of the β/A4 amyloid precursor protein. Identification of a cleavage site in cultured mammalian cells. J Biol Chem 266: 16960–16964
Wasco W, Bupp K, Magendantz M, Gusella JF, Tanzi RE, Solomon F (1992) Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid-beta-protein precursor. Proc Natl Acad Sci USA 89: 10758–10762
Wasco W, Gurubhagavatula S, Paradis Md, Romano DM, Sisodia SS, Hyman BT, Neve RL, Tanzi RE (1993) Isolation and characterization of APLP2 encoding a homologue of the Alzheimer’s associated amyloid β protein precursor. Nature Genetics, 5: 95–99
Weidemann A, König G, Bunke D, Fischer P, Salbaum JM, Masters CL, Beyreuther K (1989) Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell 57: 115–126
Wenk GL, Pierce DJ, Struble RG, Price DL, Cork LC (1989) Age-related changes in multiple neurotransmitter systems in the monkey brain. Neurobiol Aging 10: 11–19
Wisniewski T, Frangione B (1992) Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett 135: 235–238
Wisniewski HM, Terry RD (1973a) Morphology of the aging brain, human and animal. Prog Brain Res 40:167–186
Wisniewski HM, Terry RD (1973b) Reexamination of the pathogenesis of the senile plaque. In: Zimmerman HM (ed) Progress in neuropathology. Vol II New York, Grune & Stratton, pp 1–26
Wisniewski HM, Ghetti B, Terry RD (1973) Neuritic (senile) plaques and filamentous changes in aged rhesus monkeys. J Neuropathol Exp Neurol 32: 566–584
Wisniewski KE, Wisniewski HM, and Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 17: 278–282
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Price, D.L. et al. (1994). Amyloid in Alzheimer’s Disease and Animal Models. In: Masters, C.L., Beyreuther, K., Trillet, M., Christen, Y. (eds) Amyloid Protein Precursor in Development, Aging and Alzheimer’s Disease. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-01135-5_15
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