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Gene Review

APLP2  -  amyloid beta (A4) precursor-like protein 2

Homo sapiens

Synonyms: APLP-2, APPH, APPL2, Amyloid protein homolog, Amyloid-like protein 2, ...
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Disease relevance of APLP2

  • Our results demonstrate species (i.e., genetic) differences in the response to TD-induced damage and support a role for APP and APLP2 in the response to brain injury [1].
  • Our results suggest that even though APLP1 and APLP2 cannot generate Abeta, they may potentially contribute to the pathology of AD by generating peptide fragments whose toxicity is comparable to that of APPC31 [2].
  • These findings show that diverse fibrillogenic peptides can induce accumulation of APP and APLP2 and this mechanism could contribute to pathogenesis in neurodegenerative disorders [3].
  • In this paper we show that APLP1 and APLP2 mRNA expression is upregulated during RA-induced differentiation of human SH-SY5Y neuroblastoma cells [4].
  • Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease [5].

Psychiatry related information on APLP2

  • These data uncover a novel biological function for APP and APLP2 in copper efflux and provide a new conceptual framework for the formerly diverging theories of copper supplementation and chelation in the treatment of Alzheimer's disease [6].
  • The aetiology and pathogenesis of this progressive dementia is poorly understood, but symptomatic disease is associated histopathologically with amyloid plaques, neurofibrillary tangles and neuronal loss primarily in the temporal lobe and neocortex of the brain [7].
  • We previously showed that mice over-expressing a human mutated form of APP (APP(V717F)) display age-dependent recognition memory deficits associated with the progression of amyloid deposition [8].
  • Plasma levels of amyloid beta 40 and 42 are independent from ApoE genotype and mental retardation in Down syndrome [9].

High impact information on APLP2


Chemical compound and disease context of APLP2


Biological context of APLP2

  • The rapid kinetics for turnover of APP and APLP2 predict a sensitive balance of synthesis, transport, and elimination rates that may be critical to normal neuronal functions and metabolic fates of these proteins [17].
  • Serotonin also stimulated the release of the APLP2 ectodomain, suggesting that additional members of the APP multigene family are processed via similar regulated pathways [18].
  • A minimal region that includes sequences 99 bp upstream of the predominant transcription start site of the APLP2 promoter was sufficient to direct high levels of CAT expression [19].
  • The APLP2 promoter lacks a typical TATA box, is GC-rich, and contains several sequences for transcription factor binding [19].
  • Here we report on the expression of APP and its homologue, the amyloid precursor like protein 2 (APLP2), during cutaneous wound repair using a full-thickness excisional wound healing model in mice [20].

Anatomical context of APLP2

  • Moreover, we show that trans-interaction of APP family proteins promotes cell-cell adhesion in a homo- and heterotypic fashion and that endogenous APLP2 is required for cell-cell adhesion in mouse embryonic fibroblasts [21].
  • In rats, TD-induced cell degeneration is accompanied by an accumulation of amyloid precursor protein (APP)/amyloid precursor-like protein 2 (APLP2) immunoreactivity in abnormal neurites and perikarya along the periphery of, or scattered within, the lesion [1].
  • We report that in stably transfected Chinese hamster ovary and transiently transfected African green monkey kidney (COS-1) cells, APLP2 is modified by glycosaminoglycan (GAG) addition [22].
  • Overexpression of BACE in cultured cells led to increased APLP2 processing [23].
  • Immunocytochemically, all proliferation competent keratinocytes of the normal as well as the wound site epidermis showed increased expression of APP but not of APLP2 [20].

Associations of APLP2 with chemical compounds

  • Presynaptic APP and APLP2 are sialylated and N- and O-glycosylated, and some also carry chondroitin sulfate glycosaminoglycan and/or dermatan sulfate glycosaminoglycan [17].
  • Amyloid precursor-like protein 2 (APLP2) is modified by the addition of chondroitin sulfate glycosaminoglycan at a single site [22].
  • Contained within this heterologous region is a predicted CS modification site, ENEGSGMAEQ (APLP2 residues 610-619); APLP2 polypeptides harboring a serine-to-alanine substitution at position 614 fail to undergo CS GAG modification [22].
  • We suggest that CS GAG modification of a subset of APP and APLP2 isoforms represents a means of generating functional diversity for these polypeptides [24].
  • Analysis of APLP2 expression revealed regulated alternative splicing of the Kunitz protease inhibitor domain (KPI, homologous to exon 7 of APP) and a non-homologous insert of 12 amino acids on the NH2-terminal side of the transmembrane domain [25].

Physical interactions of APLP2

  • Elevated BACE1 expression coupled with increased deposition provides functional evidence for beta-secretase as a primary effector in regional amyloid deposition in the AD brain [26].
  • Characterization of an amyloid precursor protein-binding protein Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains [27].
  • Fe65 and X11beta co-localize with and compete for binding to the amyloid precursor protein [28].
  • Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity [29].
  • Like APP, APLP2 contains a cytoplasmic domain predicted to couple with the GTP-binding protein G(o) indicating that it may be an additional cell surface activator of this G protein [30].

Enzymatic interactions of APLP2


Co-localisations of APLP2


Regulatory relationships of APLP2


Other interactions of APLP2


Analytical, diagnostic and therapeutic context of APLP2


  1. Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency. Calingasan, N.Y., Gandy, S.E., Baker, H., Sheu, K.F., Smith, J.D., Lamb, B.T., Gearhart, J.D., Buxbaum, J.D., Harper, C., Selkoe, D.J., Price, D.L., Sisodia, S.S., Gibson, G.E. Am. J. Pathol. (1996) [Pubmed]
  2. Caspase cleavage of members of the amyloid precursor family of proteins. Galvan, V., Chen, S., Lu, D., Logvinova, A., Goldsmith, P., Koo, E.H., Bredesen, D.E. J. Neurochem. (2002) [Pubmed]
  3. Diverse fibrillar peptides directly bind the Alzheimer's amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation. White, A.R., Maher, F., Brazier, M.W., Jobling, M.F., Thyer, J., Stewart, L.R., Thompson, A., Gibson, R., Masters, C.L., Multhaup, G., Beyreuther, K., Barrow, C.J., Collins, S.J., Cappai, R. Brain Res. (2003) [Pubmed]
  4. Increased gene expression of beta-amyloid precursor protein and its homologues APLP1 and APLP2 in human neuroblastoma cells in response to retinoic acid. Beckman, M., Iverfeldt, K. Neurosci. Lett. (1997) [Pubmed]
  5. Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. Rumble, B., Retallack, R., Hilbich, C., Simms, G., Multhaup, G., Martins, R., Hockey, A., Montgomery, P., Beyreuther, K., Masters, C.L. N. Engl. J. Med. (1989) [Pubmed]
  6. Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer's disease. Treiber, C., Simons, A., Strauss, M., Hafner, M., Cappai, R., Bayer, T.A., Multhaup, G. J. Biol. Chem. (2004) [Pubmed]
  7. Amyloid plaques, neurofibrillary tangles and neuronal loss in brains of transgenic mice overexpressing a C-terminal fragment of human amyloid precursor protein. Kawabata, S., Higgins, G.A., Gordon, J.W. Nature (1991) [Pubmed]
  8. Behavioral deficits in APP(V717F) transgenic mice deficient for the apolipoprotein E gene. Dodart, J.C., Mathis, C., Bales, K.R., Paul, S.M., Ungerer, A. Neuroreport (2000) [Pubmed]
  9. Plasma levels of amyloid beta 40 and 42 are independent from ApoE genotype and mental retardation in Down syndrome. Cavani, S., Tamaoka, A., Moretti, A., Marinelli, L., Angelini, G., Di Stefano, S., Piombo, G., Cazzulo, V., Matsuno, S., Shoji, S., Furiya, Y., Zaccheo, D., Dagna-Bricarelli, F., Tabaton, M., Mori, H. Am. J. Med. Genet. (2000) [Pubmed]
  10. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Garlanda, C., Bottazzi, B., Bastone, A., Mantovani, A. Annu. Rev. Immunol. (2005) [Pubmed]
  11. Emerging principles of conformation-based prion inheritance. Chien, P., Weissman, J.S., DePace, A.H. Annu. Rev. Biochem. (2004) [Pubmed]
  12. Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Harper, J.D., Lansbury, P.T. Annu. Rev. Biochem. (1997) [Pubmed]
  13. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Rovelet-Lecrux, A., Hannequin, D., Raux, G., Le Meur, N., Laquerrière, A., Vital, A., Dumanchin, C., Feuillette, S., Brice, A., Vercelletto, M., Dubas, F., Frebourg, T., Campion, D. Nat. Genet. (2006) [Pubmed]
  14. Nicotine modulates expression of amyloid precursor protein and amyloid precursor-like protein 2 in mouse brain and in SH-SY5Y neuroblastoma cells. Gutala, R., Wang, J., Hwang, Y.Y., Haq, R., Li, M.D. Brain Res. (2006) [Pubmed]
  15. Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction. Adlerz, L., Beckman, M., Holback, S., Tehranian, R., Cortés Toro, V., Iverfeldt, K. Brain Res. Mol. Brain Res. (2003) [Pubmed]
  16. Kunitz protease inhibitor-containing amyloid beta protein precursor immunoreactivity in Alzheimer's disease. Hyman, B.T., Tanzi, R.E., Marzloff, K., Barbour, R., Schenk, D. J. Neuropathol. Exp. Neurol. (1992) [Pubmed]
  17. Post-translational processing and turnover kinetics of presynaptically targeted amyloid precursor superfamily proteins in the central nervous system. Lyckman, A.W., Confaloni, A.M., Thinakaran, G., Sisodia, S.S., Moya, K.L. J. Biol. Chem. (1998) [Pubmed]
  18. Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. Nitsch, R.M., Deng, M., Growdon, J.H., Wurtman, R.J. J. Biol. Chem. (1996) [Pubmed]
  19. The mouse APLP2 gene. Chromosomal localization and promoter characterization. von Koch, C.S., Lahiri, D.K., Mammen, A.L., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Sisodia, S. J. Biol. Chem. (1995) [Pubmed]
  20. Expression and potential function of beta-amyloid precursor proteins during cutaneous wound repair. Kummer, C., Wehner, S., Quast, T., Werner, S., Herzog, V. Exp. Cell Res. (2002) [Pubmed]
  21. Homo- and heterodimerization of APP family members promotes intercellular adhesion. Soba, P., Eggert, S., Wagner, K., Zentgraf, H., Siehl, K., Kreger, S., Löwer, A., Langer, A., Merdes, G., Paro, R., Masters, C.L., Müller, U., Kins, S., Beyreuther, K. EMBO J. (2005) [Pubmed]
  22. Amyloid precursor-like protein 2 (APLP2) is modified by the addition of chondroitin sulfate glycosaminoglycan at a single site. Thinakaran, G., Sisodia, S.S. J. Biol. Chem. (1994) [Pubmed]
  23. BACE (beta-secretase) modulates the processing of APLP2 in vivo. Pastorino, L., Ikin, A.F., Lamprianou, S., Vacaresse, N., Revelli, J.P., Platt, K., Paganetti, P., Mathews, P.M., Harroch, S., Buxbaum, J.D. Mol. Cell. Neurosci. (2004) [Pubmed]
  24. Novel regulation of chondroitin sulfate glycosaminoglycan modification of amyloid precursor protein and its homologue, APLP2. Thinakaran, G., Slunt, H.H., Sisodia, S.S. J. Biol. Chem. (1995) [Pubmed]
  25. APP gene family: unique age-associated changes in splicing of Alzheimer's betaA4-amyloid protein precursor. Sandbrink, R., Masters, C.L., Beyreuther, K. Neurobiol. Dis. (1994) [Pubmed]
  26. Altered amyloid-beta metabolism and deposition in genomic-based beta-secretase transgenic mice. Chiocco, M.J., Kulnane, L.S., Younkin, L., Younkin, S., Evin, G., Lamb, B.T. J. Biol. Chem. (2004) [Pubmed]
  27. Characterization of an amyloid precursor protein-binding protein Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains. Tanahashi, H., Tabira, T. Biochem. J. (2002) [Pubmed]
  28. Fe65 and X11beta co-localize with and compete for binding to the amyloid precursor protein. Lau, K.F., McLoughlin, D.M., Standen, C.L., Irving, N.G., Miller, C.C. Neuroreport (2000) [Pubmed]
  29. Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity. Koldamova, R.P., Lefterov, I.M., Lefterova, M.I., Lazo, J.S. Biochemistry (2001) [Pubmed]
  30. Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid beta protein precursor. Wasco, W., Gurubhagavatula, S., Paradis, M.D., Romano, D.M., Sisodia, S.S., Hyman, B.T., Neve, R.L., Tanzi, R.E. Nat. Genet. (1993) [Pubmed]
  31. P2Y2 nucleotide receptors enhance alpha-secretase-dependent amyloid precursor protein processing. Camden, J.M., Schrader, A.M., Camden, R.E., González, F.A., Erb, L., Seye, C.I., Weisman, G.A. J. Biol. Chem. (2005) [Pubmed]
  32. ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site. Hussain, I., Powell, D.J., Howlett, D.R., Chapman, G.A., Gilmour, L., Murdock, P.R., Tew, D.G., Meek, T.D., Chapman, C., Schneider, K., Ratcliffe, S.J., Tattersall, D., Testa, T.T., Southan, C., Ryan, D.M., Simmons, D.L., Walsh, F.S., Dingwall, C., Christie, G. Mol. Cell. Neurosci. (2000) [Pubmed]
  33. Gelatinase A possesses a beta-secretase-like activity in cleaving the amyloid protein precursor of Alzheimer's disease. LePage, R.N., Fosang, A.J., Fuller, S.J., Murphy, G., Evin, G., Beyreuther, K., Masters, C.L., Small, D.H. FEBS Lett. (1995) [Pubmed]
  34. The role of extracellular matrix in the processing of the amyloid protein precursor of Alzheimer's disease. Small, D.H., Nurcombe, V., Clarris, H., Beyreuther, K., Masters, C.L. Ann. N. Y. Acad. Sci. (1993) [Pubmed]
  35. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's beta -secretase. Bennett, B.D., Denis, P., Haniu, M., Teplow, D.B., Kahn, S., Louis, J.C., Citron, M., Vassar, R. J. Biol. Chem. (2000) [Pubmed]
  36. Immunohistochemical colocalization of amyloid precursor protein with cerebrovascular amyloid of Alzheimer's disease. Ko, L.W., Sheu, K.F., Blass, J.P. Am. J. Pathol. (1991) [Pubmed]
  37. No association between apolipoprotein E epsilon4 allele and the age of onset in type I familial amyloid polyneuropathy. Satoh, S., Tokuda, T., Ikeda, S., Sekijima, Y., Yanagisawa, N., Hidaka, H., Kametani, F. Neurosci. Lett. (1996) [Pubmed]
  38. Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. Kakimura, J., Kitamura, Y., Takata, K., Umeki, M., Suzuki, S., Shibagaki, K., Taniguchi, T., Nomura, Y., Gebicke-Haerter, P.J., Smith, M.A., Perry, G., Shimohama, S. FASEB J. (2002) [Pubmed]
  39. Apolipoprotein AI and transthyretin as components of amyloid fibrils in a kindred with apoAI Leu178His amyloidosis. de Sousa, M.M., Vital, C., Ostler, D., Fernandes, R., Pouget-Abadie, J., Carles, D., Saraiva, M.J. Am. J. Pathol. (2000) [Pubmed]
  40. Alpha 1-antichymotrypsin binding to Alzheimer A beta peptides is sequence specific and induces fibril disaggregation in vitro. Fraser, P.E., Nguyen, J.T., McLachlan, D.R., Abraham, C.R., Kirschner, D.A. J. Neurochem. (1993) [Pubmed]
  41. Amyloid beta up-regulates brain-derived neurotrophic factor production from astrocytes: rescue from amyloid beta-related neuritic degeneration. Kimura, N., Takahashi, M., Tashiro, T., Terao, K. J. Neurosci. Res. (2006) [Pubmed]
  42. Apolipoprotein E genotype regulates amyloid-beta cytotoxicity. Wilhelmus, M.M., Otte-Höller, I., Davis, J., Van Nostrand, W.E., de Waal, R.M., Verbeek, M.M. J. Neurosci. (2005) [Pubmed]
  43. Pro-domain removal in ASP-2 and the cleavage of the amyloid precursor are influenced by pH. Sidera, C., Liu, C., Austen, B. BMC Biochem. (2002) [Pubmed]
  44. Recombinant human amyloid precursor-like protein 2 (APLP2) expressed in the yeast Pichia pastoris can stimulate neurite outgrowth. Cappai, R., Mok, S.S., Galatis, D., Tucker, D.F., Henry, A., Beyreuther, K., Small, D.H., Masters, C.L. FEBS Lett. (1999) [Pubmed]
  45. A role for MAP kinase in regulating ectodomain shedding of APLP2 in corneal epithelial cells. Xu, K.P., Zoukhri, D., Zieske, J.D., Dartt, D.A., Sergheraert, C., Loing, E., Yu, F.S. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  46. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S., Mendiaz, E.A., Denis, P., Teplow, D.B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M.A., Biere, A.L., Curran, E., Burgess, T., Louis, J.C., Collins, F., Treanor, J., Rogers, G., Citron, M. Science (1999) [Pubmed]
  47. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G.S., Roses, A.D. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  48. BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Farzan, M., Schnitzler, C.E., Vasilieva, N., Leung, D., Choe, H. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  49. Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein. Guénette, S.Y., Chen, J., Jondro, P.D., Tanzi, R.E. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  50. Human IMR-32 neuroblastoma cells as a model cell line in Alzheimer's disease research. Neill, D., Hughes, D., Edwardson, J.A., Rima, B.K., Allsop, D. J. Neurosci. Res. (1994) [Pubmed]
  51. Immunohistochemical and in situ analysis of amyloid precursor-like protein-1 and amyloid precursor-like protein-2 expression in Alzheimer disease and aged control brains. McNamara, M.J., Ruff, C.T., Wasco, W., Tanzi, R.E., Thinakaran, G., Hyman, B.T. Brain Res. (1998) [Pubmed]
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