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Gene Review

App  -  amyloid beta (A4) precursor protein

Rattus norvegicus

Synonyms: ABPP, AG, APP, Alzheimer disease amyloid A4 protein homolog, Amyloid beta A4 protein, ...
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Disease relevance of App

  • There is increasing evidence linking neurodegenerative mechanisms in Alzheimer's disease (AD) and traumatic brain injury (TBI), including increased production of amyloid precursor protein (APP), and amyloid-beta (Abeta) peptide [1].
  • Pertussis toxin, which inactivates the heterotrimeric G-proteins Go and Gi, inhibits the apoptosis and DNA synthesis caused by FAD APP mutants; the apoptosis and DNA synthesis are rescued by coexpression of a pertussis toxin-insensitive Go [2].
  • In an attempt to elucidate the pathological implications of intracellular accumulation of the amyloid precursor protein (APP) in postmitotic neurons in vivo, we transferred APP695 cDNA into rat hippocampal neurons by using a replication-defective adenovirus vector [3].
  • Glial expression of the beta-amyloid precursor protein (APP) in global ischemia [4].
  • Death by antibody occurred through cell-surface APP, not through secreted APP, in a pertussis toxin-sensitive manner and was typical apoptosis, not observed in primary astrocytes or glioma cells overexpressing wtAPP, but observed in primary cortical neurons [5].

Psychiatry related information on App

  • Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact [6].
  • Our hypothesis is that APP has a role in brain development and that abnormal APP levels may be involved in dementia associated with AD and alcoholism [7].
  • After 2 weeks of APP 17-mer peptide infusion, the animals were tested for reversal learning and memory retention and were sacrificed for morphological examination of brains [8].

High impact information on App

  • Also present in the DIG fractions are the endoproteolytic fragments of presenilin-1 (PS1) and APP [9].
  • These results demonstrate that neuronal damage stimulates APP expression in adult brain and suggest that reactive astrocytes may be a source of the beta-amyloid that forms neuropathological plaques in Alzheimer's disease [10].
  • We now report that lesions of rat hippocampal neurons cause a time-dependent, long-lasting elevation of immunoreactivity for the beta-amyloid precursor protein (APP) in neighboring astrocytes, a cell type not normally containing the protein [10].
  • Although transient, the decrease in APP neosynthesis was sufficient to provoke a distinct decrease in axon and dendrite outgrowth by embryonic cortical neurons developing in vitro [11].
  • PS-1, as part of the gamma-secretase complex, is required for the intramembrane proteolysis of both amyloid precursor protein (APP) and Notch [12].

Chemical compound and disease context of App

  • We have previously demonstrated that full-length heparin stimulates the synthesis and secretion of beta-amyloid precursor protein (APP) through an amyloidogenic pathway in neuroblastoma cells [13].
  • Therefore, glutamatergic agonists that increase protein kinase C activation or decrease cyclic AMP formation may enhance the conversion of full-length APP to nonamyloidogenic APPs in Alzheimer's disease [14].
  • These results, together with the observation of a lack of deleterious effects of (1S,3R)-ACPD on the retinal neurons, support a physiological role of metabotropic glutamate receptors in mediating the release of soluble APP fragments, an action which may have important functional and therapeutic implications for Alzheimer's disease [15].
  • This experimental model is considered to be a suitable neural model to understand retinal pathology and the processing of APP in terms of the pathogenesis of AD, whereas chloroquine-induced myopathy is a useful extra neuronal model [16].
  • APP is a multifunctional transmembrane glycoprotein and the only known natural source of beta A4 peptide-the major constituent of senile plaques in Alzheimer's disease (AD) [17].

Biological context of App


Anatomical context of App

  • The 24-h time point revealed a dramatic increase in APP immunoreactivity, detected with both N- and C-terminal antibodies, in the hippocampus and cortex ipsilateral to injury [1].
  • Cholinergic lesions were combined with entorhinal cortex lesions and produced no change in APP mRNA levels compared to controls [21].
  • Hypoxic remodelling of Ca2+ mobilization in type I cortical astrocytes: involvement of ROS and pro-amyloidogenic APP processing [22].
  • Overexpression of APP actively contributes to the development of senile plaques and is considered a risk factor for the disease [23].
  • In addition, as reported previously in HUVEC cells, IL-1 beta increases the secretion of APP in PC12 cells [24].

Associations of App with chemical compounds

  • Both systems generated an APP intracellular domain, and the activity was inhibited by the gamma-secretase inhibitors l-685,458 or Compound E [25].
  • The purified protein migrated on polyacrylamide gels as a doublet of apparent molecular mass 100-120 kDa, although the predicted molecular mass of its constituent amino acids is 76 kDa. beta-APP clearly behaves anomalously in gel electrophoresis [26].
  • Imipramine or citalopram enhanced the level of secreted APP by 3.2- or 3.4-fold, respectively [27].
  • The acute-phase protein (APP) response is regulated by cytokines such as interleukin-6 (IL-6), interleukin-1 (IL-1) and tumor necrosis factor (TNF), but may also be influenced by malnutrition [28].
  • In both L-APLP2 and L-APP, a putative xylosyl-transferase recognition site for chondroitin sulfate glycosaminoglycan attachment is present that is interrupted in APP and APLP2 isoforms expressing APP exon 15 or the 12 aa exon of APLP2 [20].

Enzymatic interactions of App


Regulatory relationships of App


Other interactions of App

  • We previously demonstrated that Fe65 protein is one of the ligands of the cytoplasmic domain of beta-amyloid precursor protein (APP) [31].
  • Fe65L2 is able to interact, both in vitro and in vivo, with the intracellular domain of APP [31].
  • Expression of c-Fos and c-Myc and deposition of beta-APP in neurons in the adult rat brain as a result of exposure to short-lasting impulse noise [32].
  • Here, rat brains were investigated immunohistochemically for the expression of c-Fos, c-Myc, and beta-APP during the first 3 weeks postexposure to impulse noise of 198 or 202 dB [32].
  • Accelerated accumulation of N- and C-terminal beta APP fragments and delayed recovery of microtubule-associated protein 1B expression following stroke in aged rats [33].

Analytical, diagnostic and therapeutic context of App


  1. Changes in expression of amyloid precursor protein and interleukin-1beta after experimental traumatic brain injury in rats. Ciallella, J.R., Ikonomovic, M.D., Paljug, W.R., Wilbur, Y.I., Dixon, C.E., Kochanek, P.M., Marion, D.W., DeKosky, S.T. J. Neurotrauma (2002) [Pubmed]
  2. DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. McPhie, D.L., Coopersmith, R., Hines-Peralta, A., Chen, Y., Ivins, K.J., Manly, S.P., Kozlowski, M.R., Neve, K.A., Neve, R.L. J. Neurosci. (2003) [Pubmed]
  3. Degeneration in vivo of rat hippocampal neurons by wild-type Alzheimer amyloid precursor protein overexpressed by adenovirus-mediated gene transfer. Nishimura, I., Uetsuki, T., Dani, S.U., Ohsawa, Y., Saito, I., Okamura, H., Uchiyama, Y., Yoshikawa, K. J. Neurosci. (1998) [Pubmed]
  4. Glial expression of the beta-amyloid precursor protein (APP) in global ischemia. Banati, R.B., Gehrmann, J., Wiessner, C., Hossmann, K.A., Kreutzberg, G.W. J. Cereb. Blood Flow Metab. (1995) [Pubmed]
  5. Antibody-regulated neurotoxic function of cell-surface beta-amyloid precursor protein. Sudo, H., Jiang, H., Yasukawa, T., Hashimoto, Y., Niikura, T., Kawasumi, M., Matsuda, S., Takeuchi, Y., Aiso, S., Matsuoka, M., Murayama, Y., Nishimoto, I. Mol. Cell. Neurosci. (2000) [Pubmed]
  6. Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact. Shivers, B.D., Hilbich, C., Multhaup, G., Salbaum, M., Beyreuther, K., Seeburg, P.H. EMBO J. (1988) [Pubmed]
  7. Developmental expression of the beta-amyloid precursor protein and heat-shock protein 70 in the cerebral hemisphere region of the rat brain. Lahiri, D.K., Nall, C., Chen, D., Zaphiriou, M., Morgan, C., Nurnberger, J.I. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  8. Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. Roch, J.M., Masliah, E., Roch-Levecq, A.C., Sundsmo, M.P., Otero, D.A., Veinbergs, I., Saitoh, T. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  9. A detergent-insoluble membrane compartment contains A beta in vivo. Lee, S.J., Liyanage, U., Bickel, P.E., Xia, W., Lansbury, P.T., Kosik, K.S. Nat. Med. (1998) [Pubmed]
  10. Expression of beta-amyloid precursor protein in reactive astrocytes following neuronal damage. Siman, R., Card, J.P., Nelson, R.B., Davis, L.G. Neuron (1989) [Pubmed]
  11. Downregulation of amyloid precursor protein inhibits neurite outgrowth in vitro. Allinquant, B., Hantraye, P., Mailleux, P., Moya, K., Bouillot, C., Prochiantz, A. J. Cell Biol. (1995) [Pubmed]
  12. Specific inhibition of CBP/beta-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation. Teo, J.L., Ma, H., Nguyen, C., Lam, C., Kahn, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. Heparin oligosaccharides that pass the blood-brain barrier inhibit beta-amyloid precursor protein secretion and heparin binding to beta-amyloid peptide. Leveugle, B., Ding, W., Laurence, F., Dehouck, M.P., Scanameo, A., Cecchelli, R., Fillit, H. J. Neurochem. (1998) [Pubmed]
  14. Metabotropic glutamate receptors increase amyloid precursor protein processing in astrocytes: inhibition by cyclic AMP. Lee, R.K., Wurtman, R.J. J. Neurochem. (1997) [Pubmed]
  15. Up-regulation of soluble amyloid precursor protein fragment secretion in the rat retina in vivo by metabotropic glutamate receptor stimulation. Croucher, M.J., Patel, H., Walsh, D.T., Moncaster, J.A., Gentleman, S.M., Fazal, A., Jen, L.S. Neuroreport (2003) [Pubmed]
  16. Amyloid precursor protein, A beta and amyloid-associated proteins involved in chloroquine retinopathy in rats--immunopathological studies. Yoshida, T., Fukatsu, R., Tsuzuki, K., Aizawa, Y., Hayashi, Y., Sasaki, N., Takamaru, Y., Fujii, N., Takahata, N. Brain Res. (1997) [Pubmed]
  17. Two types of amyloid precursor protein (APP) mRNA in rat glioma cell lines: upregulation via a cyclic AMP-dependent pathway. Gegelashvili, G., Bock, E., Schousboe, A., Linnemann, D. Brain Res. Mol. Brain Res. (1996) [Pubmed]
  18. Nuclear factors interacting with an interleukin-6 responsive element of rat alpha 2-macroglobulin gene. Ito, T., Tanahashi, H., Misumi, Y., Sakaki, Y. Nucleic Acids Res. (1989) [Pubmed]
  19. Age-dependent differential regulation of genes encoding APP and alpha-synuclein in hippocampal synaptic plasticity. Stéphan, A., Davis, S., Salin, H., Dumas, S., Mallet, J., Laroche, S. Hippocampus. (2002) [Pubmed]
  20. APP gene family. Alternative splicing generates functionally related isoforms. Sandbrink, R., Masters, C.L., Beyreuther, K. Ann. N. Y. Acad. Sci. (1996) [Pubmed]
  21. Expression of amyloid precursor protein, tau and presenilin RNAs in rat hippocampus following deafferentation lesions. Ramirez, M.J., Heslop, K.E., Francis, P.T., Rattray, M. Brain Res. (2001) [Pubmed]
  22. Hypoxic remodelling of Ca2+ mobilization in type I cortical astrocytes: involvement of ROS and pro-amyloidogenic APP processing. Smith, I.F., Boyle, J.P., Green, K.N., Pearson, H.A., Peers, C. J. Neurochem. (2004) [Pubmed]
  23. Brain-derived neurotrophic factor stimulates beta-amyloid gene promoter activity by a Ras-dependent/AP-1-independent mechanism in SH-SY5Y neuroblastoma cells. Ruiz-León, Y., Pascual, A. J. Neurochem. (2001) [Pubmed]
  24. Enhanced processing of APP induced by IL-1 beta can be reduced by indomethacin and nordihydroguaiaretic acid. Dash, P.K., Moore, A.N. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  25. Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. Hansson, C.A., Frykman, S., Farmery, M.R., Tjernberg, L.O., Nilsberth, C., Pursglove, S.E., Ito, A., Winblad, B., Cowburn, R.F., Thyberg, J., Ankarcrona, M. J. Biol. Chem. (2004) [Pubmed]
  26. Purification and tissue level of the beta-amyloid peptide precursor of rat brain. Potempska, A., Styles, J., Mehta, P., Kim, K.S., Miller, D.L. J. Biol. Chem. (1991) [Pubmed]
  27. Imipramine and citalopram facilitate amyloid precursor protein secretion in vitro. Pákáski, M., Bjelik, A., Hugyecz, M., Kása, P., Janka, Z., Kálmán, J. Neurochem. Int. (2005) [Pubmed]
  28. Induction and modulation of acute-phase response by protein malnutrition in rats: comparative effect of systemic and localized inflammation on interleukin-6 and acute-phase protein synthesis. Lyoumi, S., Tamion, F., Petit, J., Déchelotte, P., Dauguet, C., Scotté, M., Hiron, M., Leplingard, A., Salier, J.P., Daveau, M., Lebreton, J.P. J. Nutr. (1998) [Pubmed]
  29. Inhibition of histone deacetylation enhances the neurotoxicity induced by the C-terminal fragments of amyloid precursor protein. Kim, H.S., Kim, E.M., Kim, N.J., Chang, K.A., Choi, Y., Ahn, K.W., Lee, J.H., Kim, S., Park, C.H., Suh, Y.H. J. Neurosci. Res. (2004) [Pubmed]
  30. Endogenous presenilin-1 targets to endocytic rather than biosynthetic compartments. Lah, J.J., Levey, A.I. Mol. Cell. Neurosci. (2000) [Pubmed]
  31. Fe65L2: a new member of the Fe65 protein family interacting with the intracellular domain of the Alzheimer's beta-amyloid precursor protein. Duilio, A., Faraonio, R., Minopoli, G., Zambrano, N., Russo, T. Biochem. J. (1998) [Pubmed]
  32. Expression of c-Fos and c-Myc and deposition of beta-APP in neurons in the adult rat brain as a result of exposure to short-lasting impulse noise. Säljö, A., Bao, F., Shi, J., Hamberger, A., Hansson, H.A., Haglid, K.G. J. Neurotrauma (2002) [Pubmed]
  33. Accelerated accumulation of N- and C-terminal beta APP fragments and delayed recovery of microtubule-associated protein 1B expression following stroke in aged rats. Badan, I., Dinca, I., Buchhold, B., Suofu, Y., Walker, L., Gratz, M., Platt, D., Kessler, C.H., Popa-Wagner, A. Eur. J. Neurosci. (2004) [Pubmed]
  34. Interaction of Tau with Fe65 links tau to APP. Barbato, C., Canu, N., Zambrano, N., Serafino, A., Minopoli, G., Ciotti, M.T., Amadoro, G., Russo, T., Calissano, P. Neurobiol. Dis. (2005) [Pubmed]
  35. Reciprocal control of inflammatory cytokines, IL-1 and IL-6, and beta-amyloid production in cultures. Del Bo, R., Angeretti, N., Lucca, E., De Simoni, M.G., Forloni, G. Neurosci. Lett. (1995) [Pubmed]
  36. Polychlorinated biphenyls alter expression of alpha-synuclein, synaptophysin and parkin in the rat brain. Malkiewicz, K., Mohammed, R., Folkesson, R., Winblad, B., Szutowski, M., Benedikz, E. Toxicol. Lett. (2006) [Pubmed]
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