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The role of APP in Alzheimer’s disease

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DOI: 10.4236/aad.2013.22008    2,862 Downloads   6,375 Views   Citations


Alzheimer’s disease (AD) is one of the most significant neurodegenerative disorders in terms of both severity and cost. Despite being defined over a century ago, there is currently no cure to this disease that affects an increasing elderly population. The amyloid precursor protein (APP) has been shown to play an important role in AD progression. The amyloid β peptide (Aβ), which accumulates in senile plaques, a central etiological AD factor, is a proteolytic product from APP by the enzymatic action of β- and γ-secretases. In this review, we summarize the current knowledge of the processing and physiological functions of APP, and the involvement of APP and Aβ in AD.

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Pung, L. , Wang, X. , Li, M. and Xue, L. (2013) The role of APP in Alzheimer’s disease. Advances in Alzheimer's Disease, 2, 60-65. doi: 10.4236/aad.2013.22008.


[1] Hebert, L.E., Scherr, P.A., Bienias, J.L., Bennett, D.A. and Evans, D.A. (2003) Alzheimer disease in the US population: Prevalence estimates using the 2000 census. Archives of Neurology, 60, 1119-1122. doi:10.1001/archneur.60.8.1119
[2] DeKosky, S.T. and Scheff, S.W. (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: Correlation with cognitive severity. Annals of Neurology, 27, 457-464. doi.:10.1002/ana.410270502
[3] Bouras, C., Hof, P.R., Giannakopoulos, P., Michel, J.P. and Morrison, J.H. (1994) Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: A quantitative evaluation of a one-year autopsy population from a geriatric hospital. Cereb Cortex, 4, 138-150. doi:10.1093/cercor/4.2.138
[4] Trojanowski, J.Q. and Lee, V.M. (1994) Paired helical filament tau in Alzheimer’s disease. The kinase connection. The American Journal of Pathology, 144, 449-453.
[5] Goedert, M., Spillantini, M.G. and Crowther, R.A. (1991) Tau proteins and neurofibrillary degeneration. Brain Pathology, 1, 279-286. doi:10.1111/j.1750-3639.1991.tb00671.x
[6] Alzheimer, A., Stelzmann, R.A., Schnitzlein, H.N. and Murtagh, F.R. (1995) An English translation of Alzheimer’s 1907 paper, Uber eine eigenartige Erkankung der Hirnrinde. Clinical Anatomy, 8, 429-431. doi:10.1002/ca.980080612
[7] Glenner, G.G. and Wong, C.W. (1984) Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical and Biophysical Research Communications, 120, 885-890. doi:10.1016/S0006-291X(84)80190-4
[8] Kang, J., Lemaire, H.G., Unterbeck, A., Salbaum, J.M., Masters, C.L., Grzeschik, K.H., Multhaup, G., Beyreuther, K. and Muller-Hill, B. (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature, 325, 733-736. doi:10.1038/325733a0
[9] Daigle, I. and Li, C. (1993) Apl-1, a Caenorhabditis elegans gene encoding a protein related to the human β-amyloid protein precursor. Proceedings of the National Academy of Sciences of the United States of America, 90, 12045-12049. doi:10.1073/pnas.90.24.12045
[10] Rosen, D.R., Martin-Morris, L., Luo, L.Q. and White, K. (1989) A Drosophila gene encoding a protein resembling the human β-amyloid protein precursor. Proceedings of the National Academy of Sciences of the United States of America, 86, 2478-2482. doi:10.1073/pnas.86.7.2478
[11] Wasco, W., Bupp, K., Magendantz, M., Gusella, J.F., Tanzi, R.E. and Solomon, F. (1992) Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid β protein precursor. Proceedings of the National Academy of Sciences of the United States of America, 89, 10758-10762. doi:10.1073/pnas.89.22.10758
[12] Wasco, W., Gurubhagavatula, S., Paradis, M.D., Romano, D.M., Sisodia, S.S., Hyman, B.T., Neve, R.L. and Tanzi, R.E. (1993) Isolation and characterization of APLP2 encoding a homologue of the Alzheimer’s associated amyloid β protein precursor. Nature Genetics, 5, 95-100. doi:10.1038/ng0993-95
[13] Sprecher, C.A., Grant, F.J., Grimm, G., O'Hara, P.J., Norris, F., Norris, K. and Foster, D.C. (1993) Molecular cloning of the cDNA for a human amyloid precursor protein homolog: Evidence for a multigene family. Biochemistry, 32, 4481-4486. doi:10.1021/bi00068a002
[14] Bayer, T.A., Cappai, R., Masters, C.L., Beyreuther, K. and Multhaup, G. (1999) It all sticks together—The APP-related family of proteins and Alzheimer’s disease. Molecular Psychiatry, 4, 524-528. doi:10.1038/
[15] Tanaka, S., Shiojiri, S., Takahashi, Y., Kitaguchi, N., Ito, H., Kameyama, M., Kimura, J., Nakamura, S. and Ueda, K. (1989) Tissue-specific expression of three types of β-protein precursor mRNA: Enhancement of protease inhibitor-harboring types in Alzheimer’s disease brain. Biochemical and Biophysical Research Communications, 165, 1406-1414. doi:10.1016/0006-291X(89)92760-5
[16] Sola, C., Mengod, G., Probst, A. and Palacios, J.M. (1993) Differential regional and cellular distribution of β-amyloid precursor protein messenger RNAs containing and lacking the Kunitz protease inhibitor domain in the brain of human, rat and mouse. Neuroscience, 53, 267-295. doi:10.1016/0306-4522(93)90304-X
[17] Ponte, P., Gonzalez-DeWhitt, P., Schilling, J., Miller, J., Hsu, D., Greenberg, B., Davis, K., Wallace, W., Lieberburg, I. and Fuller, F. (1988) A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature, 331, 525-527. doi:10.1038/331525a0
[18] Tanzi, R.E., McClatchey, A.I., Lamperti, E.D., Villa-Komaroff, L., Gusella, J.F. and Neve, R.L. (1988) Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer’s disease. Nature, 331, 528-530. doi:10.1038/331528a0
[19] Kitaguchi, N., Takahashi, Y., Tokushima, Y., Shiojiri, S. and Ito, H. (1988) Novel precursor of Alzheimer’s disease amyloid protein shows protease inhibitory activity. Nature, 331, 530-532. doi:10.1038/331530a0
[20] Zheng, H. and Koo, E.H. (2006) The amyloid precursor protein: Beyond amyloid. Molecular Neurodegeneration, 1, 5. doi:10.1186/1750-1326-1-5
[21] Selkoe, D.J. (1991) The molecular pathology of Alzheimer’s disease. Neuron, 6, 487-498. doi:10.1016/0896-6273(91)90052-2
[22] Shepherd, C., McCann, H. and Halliday, G.M. (2009) Variations in the neuropathology of familial Alzheimer’s disease. Acta Neuropathologica, 118, 37-52. doi:10.1007/s00401-009-0521-4
[23] Terry, R.D., Masliah, E., Salmon, D.P., Butters, N., De- Teresa, R., Hill, R., Hansen, L.A. and Katzman, R. (1991) Physical basis of cognitive alterations in Alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment. Annals of Neurology, 30, 572-580. doi:10.1002/ana.410300410
[24] Askanas, V., Engel, W.K. and Alvarez, R.B. (1992) Strong immunoreactivity of β-amyloid precursor protein, including the β-amyloid protein sequence, at human neuromuscular junctions. Neuroscience Letters, 143, 96-100. doi:10.1016/0304-3940(92)90241-X
[25] Torroja, L., Packard, M., Gorczyca, M., White, K. and Budnik, V. (1999) The Drosophila β-amyloid precursor protein homolog promotes synapse differentiation at the neuromuscular junction. The Journal of Neuroscience, 19, 7793-7803.
[26] Wang, B., Yang, L., Wang, Z. and Zheng, H. (2007) Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. Proceedings of the National Academy of Sciences of the United States of America, 104, 14140-14145. doi:10.1073/pnas.0704070104
[27] Wang, P., Yang, G., Mosier, D.R., Chang, P., Zaidi, T., Gong, Y.D., Zhao, N.M., Dominguez, B., Lee, K.F., Gan, W.B., et al. (2005) Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. The Journal of Neuroscience, 25, 1219-1225.doi:10.1523/JNEUROSCI.4660-04.2005
[28] Wang, Z., Wang, B., Yang, L., Guo, Q., Aithmitti, N., Songyang, Z. and Zheng, H. (2009) Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. The Journal of Neuroscience, 29, 10788-10801. doi:10.1523/JNEUROSCI.2132-09.2009
[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. doi:10.1016/S0896-6273(01)00496-2
[30] 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 β-secretase and presenilin-1 requires APP. Nature, 414, 643- 648. doi:10.1038/414643a
[31] Kamal, A., Stokin, G.B., Yang, Z., Xia, C.H. and Gold- stein, 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. doi:10.1016/S0896-6273(00)00124-0
[32] Sisodia, S.S. (2002) Biomedicine. A cargo receptor mys- tery APParently solved? Science, 295, 805-807. doi:10.1126/science.1069661
[33] 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. Current Biology, 9, 489-492. doi:10.1016/S0960-9822(99)80215-2
[34] Luo, L., Tully, T. and White, K. (1992) Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron, 9, 595-605. doi:10.1016/0896-6273(92)90024-8
[35] Merdes, G., Soba, P., Loewer, A., Bilic, M.V., Beyreuther, K. and Paro, R. (2004) Interference of human and Drosophila APP and APP-like proteins with PNS development in Drosophila. The EMBO Journal, 23, 4082-4095. doi:10.1038/sj.emboj.7600413
[36] Natte, R., De Boer, W.I., Maat-Schieman, M.L., Baelde, H.J., Vinters, H.V., Roos, R.A. and van Duinen, S.G. (1999) Amyloid β precursor protein-mRNA is expressed throughout cerebral vessel walls. Brain Research, 828, 179-183. doi:10.1016/S0006-8993(99)01361-X
[37] Girouard, H. and Iadecola, C. (2006) Neurovascular cou- pling in the normal brain and in hypertension, stroke, and Alzheimer disease. Journal of Applied Physiology, 100, 328-335.doi:10.1152/japplphysiol.00966.2005
[38] Miao, J., Xu, F., Davis, J., Otte-Holler, I., Verbeek, M.M. and Van Nostrand, W.E. (2005) Cerebral microvascular amyloid β protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid β precursor protein. The American Journal of Pathology, 167, 505-515. doi:10.1016/S0002-9440(10)62993-8
[39] Shin, H.K., Jones, P.B., Garcia-Alloza, M., Borrelli, L., Greenberg, S.M., Bacskai, B.J., Frosch, M.P., Hyman, B.T., Moskowitz, M.A. and Ayata, C. (2007) Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy. Brain, 130, 2310- 2319. doi:10.1093/brain/awm156
[40] Takano, T., Han, X., Deane, R., Zlokovic, B. and Nedergaard, M. (2007) Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease. Annals of the New York Academy of Sciences, 1097, 40-50. doi:10.1196/annals.1379.004
[41] Dorr, A., Sahota, B., Chinta, L.V., Brown, M.E., Lai, A.Y., Ma, K., Hawkes, C.A., McLaurin, J. and Stefanovic, B. (2012) Amyloid-β-dependent compromise of microvascular structure and function in a model of Alzheimer’s disease. Brain, 135, 3039-3050. doi:10.1093/brain/aws243
[42] Karaulana, E., Gramatikoff, K. and Milev, P. (1992) Amyloid precursor protein might be a receptor for basic fibroblast growth factor. The International Journal of Neuroscience, 66, 93-95. doi:10.3109/00207459208999793
[43] Young-Pearse, T.L., Bai, J., Chang, R., Zheng, J.B., Lo- Turco, J.J. and Selkoe, D.J. (2007) A critical function for β-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. The Journal of Neuroscience, 27, 14459-14469. doi:10.1523/JNEUROSCI.4701-07.2007
[44] Mok, S.S., Sberna, G., Heffernan, D., Cappai, R., Galatis, D., Clarris, H.J., Sawyer, W.H., Beyreuther, K., Masters, C.L. and Small, D.H. (1997) Expression and analysis of heparin-binding regions of the amyloid precursor protein of Alzheimer’s disease. FEBS Letters, 415, 303-307. doi:10.1016/S0014-5793(97)01146-0
[45] Nikolaev, A., McLaughlin, T., O'Leary, D.D. and Tessier-Lavigne, M. (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature, 457, 981-989. doi:10.1038/nature07767
[46] Cao, X. and Sudhof, T.C. (2001) A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyl-transferase, Tip60. Science, 293, 115-120. doi:10.1126/science.1058783
[47] Chen, W.J., Goldstein, J.L. and Brown, M.S. (1990) NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. The Journal of Biological Chemistry, 265, 3116-3123.
[48] Perez, R.G., Soriano, S., Hayes, J.D., Ostaszewski, B., Xia, W., Selkoe, D.J., Chen, X., Stokin, G.B. and Koo, E.H. (1999) Mutagenesis identifies new signals for β-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Aβ42. The Journal of Biological Chemistry, 274, 18851-18856. doi:10.1074/jbc.274.27.18851
[49] Ring, S., Weyer, S.W., Kilian, S.B., Waldron, E., Pietrzik, C.U., Filippov, M.A., Herms, J., Buchholz, C., Eckman, C.B., Korte, M., et al. (2007) The secreted β-amyloid precursor protein ectodo-main APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiologycal abnormalities of APP-deficient mice. The Journal of Neuroscience, 27, 7817-7826. doi:10.1523/JNEUROSCI.1026-07.2007
[50] Crossgrove, J.S. et al. (2005) The choroid plexus removes β-amyloid from braincerebrospinal ?uid. Experimental Biology and Medicine (Maywood), 230, 771-776.
[51] Shibata, M. et al. (2000) Clearance of Alzheimer’s amyloid-β(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. Journal of Clinical Investigation, 106, 1489-1499. doi:10.1172/JCI10498
[52] Lambert, J.C. et al. (1998) Association at LRP gene locus with sporadic late-onset Alzheimer’s disease. Lancet, 351, 1787-1788. doi:10.1016/S0140-6736(05)78749-3
[53] Lam, F.C. et al. (2001) β-Amyloid ef?ux mediated by pglycoprotein. Journal of Neurochemistry, 76, 1121-1128. doi:10.1046/j.1471-4159.2001.00113.x
[54] Yan, S.D. et al.(2000) Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Lancet, 6, 643-651. doi:10.1038/76216
[55] Deane, R. et al. (2003) RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain. Nature Medicine, 9, 907-913. doi:10.1038/nm890
[56] Caccamo, A. et al. (2005) Age- and region-dependent alterations in Aβ-degrading enzymes: Implications for Aβ-induced disorders. Neurobiology of Aging, 26, 645- 654. doi:10.1016/j.neurobiolaging.2004.06.013
[57] Kanemitsu, H. et al. (2003) Human neprilysin is capable of degrading amyloid β peptide not only in the monomeric form but also the pathological oligomeric form. Neuroscience Letters, 350, 113-116. doi:10.1016/S0304-3940(03)00898-X
[58] Marr, R.A. et al. (2003) Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. The Journal of Neuroscience, 23, 1992-1996.
[59] Leissring, M.A. et al. (2003) Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron, 40, 1087-1093. doi:10.1016/S0896-6273(03)00787-6
[60] Goldgaber, D., Lerman, M.I., McBride, O.W., Saffiotti, U. and Gaj-dusek, D.C. (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science, 235, 877-880. doi:10.1126/science.3810169
[61] Yankner, B.A., Dawes, L.R., Fisher, S., Villa-Komaroff, L., Oster-Granite, M.L. and Neve, R.L. (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science, 245, 417-420. doi:10.1126/science.2474201
[62] Deshpande, A., Mina, E., Glabe, C. and Busciglio, J. (2006) Different conformations of amyloid β induce neurotoxicity by distinct mechanisms in human cortical neurons. The Journal of Neuroscience, 26, 6011-6018. doi:10.1523/JNEUROSCI.1189-06.2006
[63] Irizarry, M.C., Soriano, F., McNamara, M., Page, K.J., Schenk, D., Games, D. and Hyman, B.T. (1997) Aβ deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. The Journal of Neuroscience, 17, 7053-7059.
[64] Chen, G., Chen, K.S., Knox, J., Inglis, J., Bernard, A., Martin, S.J., Justice, A., McConlogue, L., Games, D., Freedman, S.B., et al. (2000) A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer’s disease. Nature, 408, 975-979. doi:10.1038/35050103
[65] Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S. and Malinow, R. (2003) APP processing and synaptic function. Neuron, 37, 925-937. doi:10.1016/S0896-6273(03)00124-7
[66] Spires, T.L. and Hyman, B.T. (2005) Transgenic models of Alzheimer’s disease: Learning from animals. NeuroRx, 2, 423-437. doi:10.1602/neurorx.2.3.423
[67] Hyman, B.T. (2011) Caspase activation without apoptosis: Insight into Aβ initiation of neurodegeneration. Nature neuroscience, 14, 5-6. doi:10.1038/nn0111-5
[68] Gervais, F.G., Xu, D., Robertson, G.S., Vaillancourt, J.P., Zhu, Y., Huang, J., LeBlanc, A., Smith, D., Rigby, M., Shearman, M.S., et al. (1999) Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-β precursor protein and amyloidogenic Aβ peptide formation. Cell, 97, 395-406. doi:10.1016/S0092-8674(00)80748-5
[69] LaFerla, F.M., Green, K.N. and Oddo, S. (2007) Intracellular amyloid-β in Alzheimer’s disease. Nature Reviews Neuroscience, 8, 499-509. doi:10.1038/nrn2168
[70] Chung, S., Lee, J., Joe, E.H. and Uhm, D.Y. (2001) β-amyloid peptide induces the expression of voltage dependent outward rectifying K+ channels in rat microglia. Neuroscience Letters, 300, 67-70. doi:10.1016/S0304-3940(01)01516-6
[71] Cho, J.H. and Johnson, G.V. (2004) Glycogen synthase kinase 3β induces caspase-cleaved tau aggregation in situ. The Journal of Biological Chemistry, 279, 54716-54723. doi:10.1074/jbc.M403364200
[72] Roberson, E.D., Scearce-Levie, K., Palop, J.J., Yan, F., Cheng, I.H., Wu, T., Gerstein, H., Yu, G.Q. and Mucke, L. (2007) Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science, 316, 750-754. doi:10.1126/science.1141736
[73] Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., Jones, R.W., Bullock, R., Love, S., Neal, J.W., et al. (2008) Long-term effects of Aβ42 immunisation in Alzheimer’s disease: Follow-up of a randomised, placebo-controlled phase I trial. Lancet, 372, 216-223. doi:10.1016/S0140-6736(08)61075-2
[74] Grant, J.L., Ghosn, E.E., Axtell, R.C., Herges, K., Kuipers, H.F., Woodling, N.S., Andreasson, K., Herzenberg, L.A. and Steinman, L. (2012) Reversal of paralysis and reduced inflammation from peripheral administration of β-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Science Translational Medicine, 4, 145ra105.

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