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Gene Review

App  -  amyloid beta (A4) precursor protein

Mus musculus

Synonyms: ABPP, AG, AL024401, APP, Abeta, ...
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Disease relevance of App


Psychiatry related information on App


High impact information on App


Chemical compound and disease context of App


Biological context of App


Anatomical context of App

  • Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M146L transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates [21].
  • Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease [22].
  • The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta 42 peptide, the main component of AD plaques [23].
  • We have previously shown that the axonal transport of APP in neurons is mediated by the direct binding of APP to the kinesin light chain subunit of kinesin-I, a microtubule motor protein [19].
  • In contrast, almost no gamma-secretase processing was observed when holo-APP or APP-C99, a direct substrate for gamma-secretase, were specifically retained in the endoplasmic reticulum (ER) by a double lysine retention motif [24].

Associations of App with chemical compounds

  • The target of lithium in this setting is GSK-3alpha, which is required for maximal processing of APP [22].
  • Conversely, inhibition of PLD1 activity by 1-butanol decreases betaAPP trafficking in both wt and PS1-deficient cells [25].
  • Rabbit and mouse vaccinations with Abeta-VLP were well tolerated and induced high-titer autoAb against Abeta, that inhibited effectively assembly of Abeta(1-42) peptides into neurotoxic fibrils in vitro [4].
  • Multiple effects of aspartate mutant presenilin 1 on the processing and trafficking of amyloid precursor protein [26].
  • Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and beta Amyloid in Mouse Microglia Cells [27].

Physical interactions of App


Enzymatic interactions of App


Co-localisations of App

  • We also found that 12-month-old PDAPP Abca1-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble Abeta [38].

Regulatory relationships of App

  • Overexpression of PLD1 in PS1wt cells promotes generation of betaAPP-containing vesicles from the trans-Golgi network [25].
  • These observations clearly indicate that X11L suppresses the amyloidogenic but not amyloidolytic processing of APP in regions of the brain such as the hippocampus, which express significant levels of X11L [39].
  • Neprilysin regulates amyloid Beta peptide levels [40].
  • Furthermore, higher levels of Numb were detected in the cortex of mice expressing mutant amyloid precursor protein (APP) relative to age-matched wild-type mice [15].
  • These results suggest that endogenously overproduced Abeta induces increased tau phosphorylation through activation of GSK-3, and that inactivation of PKC is at least one of the mechanisms involved in GSK-3 activation [41].

Other interactions of App


Analytical, diagnostic and therapeutic context of App


  1. Gene silencing analyses against amyloid precursor protein (APP) gene family by RNA interference. Sakai, T., Hohjoh, H. Cell Biol. Int. (2006) [Pubmed]
  2. PKCepsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice. Choi, D.S., Wang, D., Yu, G.Q., Zhu, G., Kharazia, V.N., Paredes, J.P., Chang, W.S., Deitchman, J.K., Mucke, L., Messing, R.O. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  3. Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1 and amyloid precursor protein transgenes. Wong, T.P., Debeir, T., Duff, K., Cuello, A.C. J. Neurosci. (1999) [Pubmed]
  4. Papillomavirus-like particles are an effective platform for amyloid-beta immunization in rabbits and transgenic mice. Zamora, E., Handisurya, A., Shafti-Keramat, S., Borchelt, D., Rudow, G., Conant, K., Cox, C., Troncoso, J.C., Kirnbauer, R. J. Immunol. (2006) [Pubmed]
  5. Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Garcia-Alloza, M., Robbins, E.M., Zhang-Nunes, S.X., Purcell, S.M., Betensky, R.A., Raju, S., Prada, C., Greenberg, S.M., Bacskai, B.J., Frosch, M.P. Neurobiol. Dis. (2006) [Pubmed]
  6. Rodent A beta modulates the solubility and distribution of amyloid deposits in transgenic mice. Jankowsky, J.L., Younkin, L.H., Gonzales, V., Fadale, D.J., Slunt, H.H., Lester, H.A., Younkin, S.G., Borchelt, D.R. J. Biol. Chem. (2007) [Pubmed]
  7. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Lazarov, O., Robinson, J., Tang, Y.P., Hairston, I.S., Korade-Mirnics, Z., Lee, V.M., Hersh, L.B., Sapolsky, R.M., Mirnics, K., Sisodia, S.S. Cell (2005) [Pubmed]
  8. Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome. Shukkur, E.A., Shimohata, A., Akagi, T., Yu, W., Yamaguchi, M., Murayama, M., Chui, D., Takeuchi, T., Amano, K., Subramhanya, K.H., Hashikawa, T., Sago, H., Epstein, C.J., Takashima, A., Yamakawa, K. Hum. Mol. Genet. (2006) [Pubmed]
  9. Amyloid plaques in Creutzfeldt-Jakob disease stain with prion protein antibodies. Kitamoto, T., Tateishi, J., Tashima, T., Takeshita, I., Barry, R.A., DeArmond, S.J., Prusiner, S.B. Ann. Neurol. (1986) [Pubmed]
  10. APP mRNA splicing is upregulated in the brain of biglycan transgenic mice. Bjelik, A., P??k??ski, M., Bereczki, E., Gonda, S., Juh??sz, A., Riman??czy, A., Zana, M., Janka, Z., S??ntha, M., K??lm??n, J. Neurochem. Int. (2007) [Pubmed]
  11. Islet amyloid and type 2 diabetes mellitus. Höppener, J.W., Ahrén, B., Lips, C.J. N. Engl. J. Med. (2000) [Pubmed]
  12. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Scherzinger, E., Lurz, R., Turmaine, M., Mangiarini, L., Hollenbach, B., Hasenbank, R., Bates, G.P., Davies, S.W., Lehrach, H., Wanker, E.E. Cell (1997) [Pubmed]
  13. The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. LaFerla, F.M., Tinkle, B.T., Bieberich, C.J., Haudenschild, C.C., Jay, G. Nat. Genet. (1995) [Pubmed]
  14. Estrogen alters amyloid precursor protein as well as dendritic and cholinergic markers in a mouse model of Down syndrome. Granholm, A.C., Sanders, L., Seo, H., Lin, L., Ford, K., Isacson, O. Hippocampus. (2003) [Pubmed]
  15. Numb modifies neuronal vulnerability to amyloid beta-peptide in an isoform-specific manner by a mechanism involving altered calcium homeostasis: implications for neuronal death in Alzheimer's disease. Chan, S.L., Pedersen, W.A., Zhu, H., Mattson, M.P. Neuromolecular Med. (2002) [Pubmed]
  16. Gleevec inhibits beta-amyloid production but not Notch cleavage. Netzer, W.J., Dou, F., Cai, D., Veach, D., Jean, S., Li, Y., Bornmann, W.G., Clarkson, B., Xu, H., Greengard, P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  17. Hyperhomocysteinemic Alzheimer's mouse model of amyloidosis shows increased brain amyloid beta peptide levels. Pacheco-Quinto, J., Rodriguez de Turco, E.B., DeRosa, S., Howard, A., Cruz-Sanchez, F., Sambamurti, K., Refolo, L., Petanceska, S., Pappolla, M.A. Neurobiol. Dis. (2006) [Pubmed]
  18. Increased expression of beta-amyloid protein precursor and microtubule-associated protein tau during the differentiation of murine embryonal carcinoma cells. Fukuchi, K., Deeb, S.S., Kamino, K., Ogburn, C.E., Snow, A.D., Sekiguchi, R.T., Wight, T.N., Piussan, H., Martin, G.M. J. Neurochem. (1992) [Pubmed]
  19. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Kamal, A., Almenar-Queralt, A., LeBlanc, J.F., Roberts, E.A., Goldstein, L.S. Nature (2001) [Pubmed]
  20. Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype. Rozmahel, R., Mount, H.T., Chen, F., Nguyen, V., Huang, J., Erdebil, S., Liauw, J., Yu, G., Hasegawa, H., Gu, Y., Song, Y.Q., Schmidt, S.D., Nixon, R.A., Mathews, P.M., Bergeron, C., Fraser, P., Westaway, D., St George-Hyslop, P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  21. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Holcomb, L., Gordon, M.N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., O'Campo, K., Hardy, J., Prada, C.M., Eckman, C., Younkin, S., Hsiao, K., Duff, K. Nat. Med. (1998) [Pubmed]
  22. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Phiel, C.J., Wilson, C.A., Lee, V.M., Klein, P.S. Nature (2003) [Pubmed]
  23. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-Wood, K., Lee, M., Seubert, P., Davis, A., Kholodenko, D., Motter, R., Sherrington, R., Perry, B., Yao, H., Strome, R., Lieberburg, I., Rommens, J., Kim, S., Schenk, D., Fraser, P., St George Hyslop, P., Selkoe, D.J. Nat. Med. (1997) [Pubmed]
  24. The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein. Cupers, P., Bentahir, M., Craessaerts, K., Orlans, I., Vanderstichele, H., Saftig, P., De Strooper, B., Annaert, W. J. Cell Biol. (2001) [Pubmed]
  25. Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons. Cai, D., Zhong, M., Wang, R., Netzer, W.J., Shields, D., Zheng, H., Sisodia, S.S., Foster, D.A., Gorelick, F.S., Xu, H., Greengard, P. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  26. Multiple effects of aspartate mutant presenilin 1 on the processing and trafficking of amyloid precursor protein. Kim, S.H., Leem, J.Y., Lah, J.J., Slunt, H.H., Levey, A.I., Thinakaran, G., Sisodia, S.S. J. Biol. Chem. (2001) [Pubmed]
  27. Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and beta Amyloid in Mouse Microglia Cells. D'Alimonte, I., Flati, V., D'Auro, M., Toniato, E., Martinotti, S., Rathbone, M.P., Jiang, S., Ballerini, P., Di Iorio, P., Caciagli, F., Ciccarelli, R. J. Immunol. (2007) [Pubmed]
  28. Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals. Li, T., Ma, G., Cai, H., Price, D.L., Wong, P.C. J. Neurosci. (2003) [Pubmed]
  29. PEN-2 enhances gamma-cleavage after presenilin heterodimer formation. Shiraishi, H., Sai, X., Wang, H.Q., Maeda, Y., Kurono, Y., Nishimura, M., Yanagisawa, K., Komano, H. J. Neurochem. (2004) [Pubmed]
  30. Secreted glypican binds to the amyloid precursor protein of Alzheimer's disease (APP) and inhibits APP-induced neurite outgrowth. Williamson, T.G., Mok, S.S., Henry, A., Cappai, R., Lander, A.D., Nurcombe, V., Beyreuther, K., Masters, C.L., Small, D.H. J. Biol. Chem. (1996) [Pubmed]
  31. Estrogen protects neuronal cells from the cytotoxicity induced by acetylcholinesterase-amyloid complexes. Bonnefont, A.B., Muñoz, F.J., Inestrosa, N.C. FEBS Lett. (1998) [Pubmed]
  32. In vivo cleavage of alpha2,6-sialyltransferase by Alzheimer beta-secretase. Kitazume, S., Nakagawa, K., Oka, R., Tachida, Y., Ogawa, K., Luo, Y., Citron, M., Shitara, H., Taya, C., Yonekawa, H., Paulson, J.C., Miyoshi, E., Taniguchi, N., Hashimoto, Y. J. Biol. Chem. (2005) [Pubmed]
  33. Growth factor receptor-bound protein 2 interaction with the tyrosine-phosphorylated tail of amyloid beta precursor protein is mediated by its Src homology 2 domain. Zhou, D., Noviello, C., D'Ambrosio, C., Scaloni, A., D'Adamio, L. J. Biol. Chem. (2004) [Pubmed]
  34. Caspase cleavage of the amyloid precursor protein modulates amyloid beta-protein toxicity. Lu, D.C., Soriano, S., Bredesen, D.E., Koo, E.H. J. Neurochem. (2003) [Pubmed]
  35. Bace1 modulates myelination in the central and peripheral nervous system. Hu, X., Hicks, C.W., He, W., Wong, P., Macklin, W.B., Trapp, B.D., Yan, R. Nat. Neurosci. (2006) [Pubmed]
  36. Amyloid beta protein toxicity mediated by the formation of amyloid-beta protein precursor complexes. Lu, D.C., Shaked, G.M., Masliah, E., Bredesen, D.E., Koo, E.H. Ann. Neurol. (2003) [Pubmed]
  37. Addition of protease inhibitors to culture medium of neuroblastoma cells induces both neurite outgrowth and phosphorylation of microtubule-associated protein MAP-1B. Díaz-Nido, J., Armas-Portela, R., Avila, J. J. Cell. Sci. (1991) [Pubmed]
  38. Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. Wahrle, S.E., Jiang, H., Parsadanian, M., Hartman, R.E., Bales, K.R., Paul, S.M., Holtzman, D.M. J. Biol. Chem. (2005) [Pubmed]
  39. Enhanced Amyloidogenic Metabolism of the Amyloid beta-Protein Precursor in the X11L-deficient Mouse Brain. Sano, Y., Syuzo-Takabatake, A., Nakaya, T., Saito, Y., Tomita, S., Itohara, S., Suzuki, T. J. Biol. Chem. (2006) [Pubmed]
  40. Neprilysin regulates amyloid Beta peptide levels. Marr, R.A., Guan, H., Rockenstein, E., Kindy, M., Gage, F.H., Verma, I., Masliah, E., Hersh, L.B. J. Mol. Neurosci. (2004) [Pubmed]
  41. Effects of endogenous beta-amyloid overproduction on tau phosphorylation in cell culture. Wang, Z.F., Li, H.L., Li, X.C., Zhang, Q., Tian, Q., Wang, Q., Xu, H., Wang, J.Z. J. Neurochem. (2006) [Pubmed]
  42. Intracellular retention of caveolin 1 in presenilin-deficient cells. Wood, D.R., Nye, J.S., Lamb, N.J., Fernandez, A., Kitzmann, M. J. Biol. Chem. (2005) [Pubmed]
  43. Interferon-{gamma} and Tumor Necrosis Factor-{alpha} Regulate Amyloid-{beta} Plaque Deposition and {beta}-Secretase Expression in Swedish Mutant APP Transgenic Mice. Yamamoto, M., Kiyota, T., Horiba, M., Buescher, J.L., Walsh, S.M., Gendelman, H.E., Ikezu, T. Am. J. Pathol. (2007) [Pubmed]
  44. Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloid beta peptides. Inability of truncated forms of PS2 with familial Alzheimer's disease mutation to increase secretion of Abeta42. Tomita, T., Tokuhiro, S., Hashimoto, T., Aiba, K., Saido, T.C., Maruyama, K., Iwatsubo, T. J. Biol. Chem. (1998) [Pubmed]
  45. An early specific cell-cell interaction occurs in the production of beta-amyloid in cell cultures. Dewji, N.N., Mukhopadhyay, D., Singer, S.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  46. Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. Beglopoulos, V., Sun, X., Saura, C.A., Lemere, C.A., Kim, R.D., Shen, J. J. Biol. Chem. (2004) [Pubmed]
  47. BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Ohno, M., Cole, S.L., Yasvoina, M., Zhao, J., Citron, M., Berry, R., Disterhoft, J.F., Vassar, R. Neurobiol. Dis. (2007) [Pubmed]
  48. Impact of different saturated fatty acid, polyunsaturated fatty acid and cholesterol containing diets on beta-amyloid accumulation in APP/PS1 transgenic mice. Oksman, M., Iivonen, H., Hogyes, E., Amtul, Z., Penke, B., Leenders, I., Broersen, L., Lütjohann, D., Hartmann, T., Tanila, H. Neurobiol. Dis. (2006) [Pubmed]
  49. Novel aspects of accumulation dynamics and A beta composition in transgenic models of AD. Lewis, H.D., Beher, D., Smith, D., Hewson, L., Cookson, N., Reynolds, D.S., Dawson, G.R., Jiang, M., Van der Ploeg, L.H., Qian, S., Rosahl, T.W., Kalaria, R.N., Shearman, M.S. Neurobiol. Aging (2004) [Pubmed]
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