Skip to main content

Advertisement

Log in

NSE-Controlled Carboxyl-Terminus of APP Gene Over-Expressing in Transgenic Mice Induces Altered Expressions in Behavior, Aβ-42, and GSK3β Binding Proteins

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Summary

The amyloid protein precursor (APP) is cleaved in its intramembranous domain by γ-secrease to generate amyloid β and a free carboxyl-terminal intracellular fragment. The carboxyl-terminal of 105 amino acids of APP (APP-C105) plays a crucial role in the neuropathology of Alzheimer’s disease (AD), but it is incompletely understand how APP-C105 overexpression interacts and regulates the brain function and Aβ-42 levels, and whether or not it is associated with the expressions of GSK3β-binding proteins. To test this, transgenic mice expressing NSE-controlled APP-C105 were produced and tested for their above phenotypes. A behavioral deficit was observed in the 9 months old transgenic mice, and western blot indicated that there was a predominant expression of APP-C105 in transgenic brains compared with those of non-transgenic brains. In parallel, APP-C105 overexpression resulted in the modulation of the Aβ-42 level, γ-secretase activity, GSK3β-binding proteins including PS1, tau, and β-catenin in the brains of the transgenic mice relative to the non-transgenic mice. Thus, altered expressions of these neuropathological phenotypes in APP-C105 transgenic mice could be useful targets in developing new therapeutic treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abe, K., and Saito, H. (2000). Amyloid Β neurotoxicity not mediated by the mitogen-activated protein kinase cascade in cultured and hippocampal and cortical neurons. Neurosci. Lett. 292:1–4.

    Article  PubMed  Google Scholar 

  • Arnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R., and van Hoesen, G. W. (1991). The topographical and neuroanatomical distribution of neurofibrillary tangles and neurotic plaques in the cerebral cortex of patient with Alzheimer’s disease. Cereb. Cortex 1:103–106.

    PubMed  Google Scholar 

  • Bard, F., Cannon, C., Barbour, R., Burke, R. L., Games, D., Grajeda, H., Guida, T., Hu, K., Hung, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Lieberburg, I., Motter, R., Nguten, M., Soriano, F., Vasquenz, N., Weiss, K., Welch, B., Seuber, P., Schenk, D., and Yednock, T. (2000). Peripherally administered antibodies agonist amyloid Β-peptide enter the nervous system and reduce pathology in a mouse model of Alzheimer’s disease. Nat. Med. 6:916–919.

    Article  PubMed  Google Scholar 

  • Cassone, A., Conti, S., Bernards, F.D., and Polonelli, L. (1997). Antibodies, killer toxins and antifungal immunoprecipitation: A lesson fromnature? Immunol. Today 18:164–169.

    Article  PubMed  Google Scholar 

  • Choi, S.H., Park, C.H., Koo, J.W., Seo, J.H., Kim, H.S., Jeong, S.J., Lee, J.H., Kim, S.S., and Suh, Y.H. (2001). Memory impairment and cholinergic dysfunction by centrally administered Abeta and carboxyl-terminal fragment of Alzheimer’s APP in mice. FASEB J. 15:1816–1818.

    Article  PubMed  Google Scholar 

  • Citron, M., Diehl, T., S., Gordon, G., Biere, A.L., Seubert, P., and Selkoe, D. J. (1996). Evidence that the 42- and 40-amino acid forms of amyloid Β protein are generated from the Β-amyloid precussor protein by different protease activities. Proc. Natl. Acad. Sci. U.S.A. 93:3170–13175.

    Article  Google Scholar 

  • Conti, S., Magliani, W., Gerloni, M., Salati, A., Dieci, E., Arseni, S., Fisicaro, P., and Polonelli, L. (1998). A transphyletic anti-infectious control strategy based on the killer phenomenon. FEMS Immunol. Med. Microbiol. 22:151–161.

    Article  PubMed  Google Scholar 

  • Doble, B.W., and Woodgett, J.R. (2003). GSK3Β: Tricks of the trade for a multi-tasking kinase. J. Cell. Sci. 116:1175–1186.

    Article  PubMed  Google Scholar 

  • Downward, J. (1998). Mechanisms and consequences of activation of protein kinase B/Akt. Curr. Opin. Cell. Biol. 10:262–267.

    Article  PubMed  Google Scholar 

  • Fitzpatrick, J.L., Mize, A.L., Wade, C.B., Harris, J.A., Shapiro, J.L., and Dorsa, D.M. (2002). Estrogen-mediated neuroprotection against Β-amyloid toxicity requires expression of estrogen receptor Α or Β and activation of the MAPK pathway. J. Neurochem. 82: 674–682.

    Article  PubMed  Google Scholar 

  • Forss-Petter, S., Denielson, P.E., Catsicas, S., Battenberg, E., Price, J., Nerenberg, M., and Sutcliffe, M. (1990). Transgenic mice expressing Β-galactosidase in mature neuron under neuron-specific enolase promoter control. Cell. 5:187–197.

    Google Scholar 

  • Gervais, F.G., Robertson, G.S., Vaillancourt, J.P., Zhu, Y., Huang, J., LeBlanc, A., Smith, D., Rigby, M., Shearman, M.S., Clarke, E.E., Zheng, H., van Der. Ploeg, L.H., Ruffolo, S.C., Thrnberry, N.A., Xanthoudakis, S., Zamboni, R.J., Roy, S., and Nicolson, D.W. (1999). Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-Β precusor protein and amyloidogenic AΒ peptide formation. Cell 97: 395–406.

    Article  PubMed  Google Scholar 

  • Haass, C., Schlossmacher, M.G., Hung, A.Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B.L., Lieberburg, I., Koo, E.H., Schenk, D., Teplow, D.B., and Selkoe, D.E. (1992). Amyloid-peptide is produced by cultured cells during normal metabolism. Nature 359:32–35.

    Article  Google Scholar 

  • Haass, C., and Stropper, B. (1999). The presenilin in Alzheimer’s disease-proteolysis hold the key. Science 286:916–919.

    Article  PubMed  Google Scholar 

  • Hwang, D.Y., Chae, K.R., Kang, T.S., Hwang, J.H., Lim, C.H., Kang, H.K., Goo, J.S., Lee, M.R., Lim, H.J., Min, S.H., Cho, J.Y., Hong, J.T., Song, C.W., Paik, S.G., Cho, J.S., and Kim, Y.K. (2002). Alterations in behavior, amyloid Β-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer’s disease. FASEB J. 16:805–813.

    Article  PubMed  Google Scholar 

  • Hwang, D.Y., Cho, J.S., Lee, S.H., Chae, K.R., Lim, H.J., Min, S.H., Seo, S.J., Song, Y.S., Song, C.W., Paik, S.G., Sheen, Y.Y., and Kim, Y.K. (2004). Aberrant expressions of pathogenic phenotypes in Alzheimer’s diseased transgenic mice carrying NSE-controlled APPsw. Exp. Neurol. 86:20– 32.

    Article  Google Scholar 

  • Ida, N., Hartmann, T., Pantel, J., Schroeder, J., Zerfass, R., Foerstel, H., Sandbrink, R., Masters, C. L., and Beyreuther, K. (1996). Analysis of heterogeneous ΒA42 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J. Biol. Chem. 271:22908–22914.

    Article  PubMed  Google Scholar 

  • Ishigura, K., Omori, A., Takematsu, M., Sato, K., Arioka, M., Uchida, T., and Imahori, K. (1992). Phosphorylation sites on tau by tau protein kinase I, a bovine derived kinase generating an epitope of paired helical filaments. Neurosci. Lett. 148:202–206.

    Article  PubMed  Google Scholar 

  • Ishgura, K., Shiratsuchi, A., Sato, S., Omori, A., Arioka, M., Kobayashi, S., Ukida, T., and Imahori, K. (1993). Glycogen synthase kinase 3Β is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett. 325:167–172.

    Article  PubMed  Google Scholar 

  • Johnson, S.A., Rogers, J., and Finch, C.E. (1989). APP695 transcript prevalence is selectively reduced during Alzheimer’s disease in cortex and hippocampus but not in cellebellum. Neurobiol. Aging 10:7557–7560.

    Google Scholar 

  • Kammesheidt, A., Boice, F.M., Spanoyannis, A.F., Cumming, B.J., Ortegon, M., Cotman, C., Vaught, J.L., and Neve, R.L. (1992). Deposition of Β/A4 immunoreactivity and neuronal pathway in transgenic mice expressing the carboxyl terminal fragment of the Alzheimer amyloid precursor in the brain. Proc. Natl. Acad. Sci. U.S.A. 89:10857–10861.

    PubMed  Google Scholar 

  • Kirschenbaum, F., Hsu, S.C., Cordell, B., and McCarthy, J.V. (2001) Glycogen synthase kinase-3Β regulates presenilin 1 C-terminal fragment levels. J. Biol. Chem. 276:30701–30707.

    Article  PubMed  Google Scholar 

  • Klafuki, H., Abramowski, D., Swoboda, R., Paganetti, P.A., and Staufenbiel, M. (1996). The carboxyl-termini of Β amyloid peptides 1-40 and 1-42 are generated by distinct γ-secretase activities J. Biol. Chem. 271:28655–28659.

    Article  PubMed  Google Scholar 

  • Liu, Z., Gastard, M., Verina, T., Bora, S., Mouton, P.R., and Koliatsos, V.E. (2001). Estrogens modulate experimentally induced apoptosis of granule cells in the adult hippocampus. J. Comp. Neurol. 44: 1–8.

    Article  Google Scholar 

  • Lovestone, S., Reynolds, C.H., Latimer, D., Davis, D.R., Anderton, B.H., Gallo, J.M., Hanger, D., Mulot, S., Marquardt, B., Stabel, S., Woodgett, J.R., and Miller, C. (1994). Alzheimer’s disease like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr. Biol. 4:1077–1086.

    Article  PubMed  Google Scholar 

  • Lucas, J.J., Hermandez, F., Gomez-Ramos, P., Moran, M.A., Hen, R., and Avila, J. (2001). Decreased nuclear Β-catenin, tau hyperphosphorylation and neurodegeration in GSK-3Β conditional transgenic mice. EMBO J. 20:27–39.

    Article  PubMed  Google Scholar 

  • Manthey, D., Heck, S., and Behi, C. (2001). Estrogen induces a rapid secretion of amyloid Β precusor protein via mitogen-activated protein kinas pathway. Eur. J. Biochem. 268:4285–4291.

    Article  PubMed  Google Scholar 

  • McDonnell, D.P., Chang, C.Y., and Norris, J.D. (2001). Capitalizing the complexities of estrogen receptors pharmacology in the quest for the perfect SERM. Ann. N.Y. Acad. Sci. 949:16–35.

    PubMed  Google Scholar 

  • McKenna, N.J., and O’Malley, B.W. (2001). Nuclear receptor, coregulator, ligands, and selective receptor modulators: Making sense of the patch work guilt. Ann. NY. Acad. Sci. 949:3–5.

    PubMed  Google Scholar 

  • Means, A.R., Comstock, J.P., Rosenfield, G.C., and O’Malley, B.W. (1972). Ovalbumin messenger RNA of chick oviduct partial charaterization, estrogen dependence, and translation in vitro. Proc. Natl. Acad. Sci. U.S.A. 69:1146–1150.

    PubMed  Google Scholar 

  • Murphy, M.P., Hickman, L.J., Eckman, C.B., Uljon, S.N., Wang, R., and Golde, T.E. (1999). γ-Secreatse, evidence for multiple proteolytic activities and influence of membrane positioning of substrate on generation of amyloid Β-peptide of varying length. J. Biol. Chem. 274:11914–11923.

    Article  PubMed  Google Scholar 

  • Nalbantoglu, J., Tirado-Santiago, G., Lahsaini, A., Poirier, J., Goncalves, O., Verge, G., Momoli, F., Welner, S.A., Massicotte, G., Julien, J.P., and Shapiro, M.L. (1997). Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 29:387(632), 500–505.

    Article  Google Scholar 

  • Oster-Granite, M.L., McPhie, D.L., Greenan, J., and Neve, R.L. (1996). Age-dependent neuronal and synaptic degeration in mice transgenic for the C Terminus of the amyloid precursor protein. J.Neurosci. 16:6732–6741.

    PubMed  Google Scholar 

  • Paech, K., Webb, P., Kuiper, G.G.J.M., Nilson, S., Gustafson, J.A., Kushner, P.J., and Scanlan, T.S. (1997). Differential ligand activation of estrogen receptors ERΑ and ERΒ at AP1 site. Science 277:1508–1510.

    Article  PubMed  Google Scholar 

  • Phiel, C.J., Wilson, C.A., Lee, V. M.-Y., and Klein, P.S. (2003). GSKΑ regulates production of AD amyloid-Β peptides. Nature 4223:435–429

    Article  Google Scholar 

  • Sato, M., Kawarabayashi, T., Shoji, M., Kobayashi, T., Tada, N., Matsubara, E., and Hiraim, S.M. (1997). Neurogeneration and gliosis in transgenic mice overexpressing a carboxyl-terminal fragment of Alzheimer amyloid-Β protein precursor. Dement. Geriatr. Cognit. Disorders 8:296–307.

    Google Scholar 

  • Schenk, D., Barbour, R., Dunn, W., Gorden, G., Grajeda, H., Guido, T., Hu, K., Hung, J., Jhnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Liao, Z., Lieberburg. I., Matter, R., Mutter, L., Soriano, F., Shopp, G., Vasquenz, N., Vandevert, C., Walker, S., Wogulis, M., Yednoclk, T., Games, D., and Seubert, P. (1999). Immunization with amyloid Β attenuates Alzheimer’s disease-like pathology in the PDAAP mouse. Nature 400:173–177.

    Article  PubMed  Google Scholar 

  • Sun, X., Sato, S., Murayama, O., Murayama, M., Park, J.M., Yamaguchi, H., and Takashima, A. (2002). Lithium inhibits amyloid secretion in COS cells transfected with amyloid precursor protein C100. Neurosci. Lett. 321:61–64.

    Article  PubMed  Google Scholar 

  • Takashima, A., Honda, T., Yasutake, K., Michael, G., Murayama, O., Murayama, M., Ishiguro, K., and Yamaguchi, H. (1998A). Activation of tau protein kinase I and glycogen synthase kinase-3Β by amyloid Β peptide (25–35) enhances phosphorylation of tau in hippocampal neurons. Neurosci. Res. 31:317–323.

    Article  Google Scholar 

  • Takeshima, A., Murayama, M., Murayama, O., Kohno, T., Honda, T., Yasutake, K., Nihonmatsu, N., Merken, M., Yamaguchi, H., Sugihara, S., and Wolozin, B. (1998B). Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc. Natl. Acad. Sci. 95:9637–9641.

    Article  Google Scholar 

  • Tesco, G., and Tanzi, R.E. (2000). GSK3Β forms a tetrameric complex with endogenous PS1-CTF/NTF and Β-catenin. Ann. New. York. Acad. Sci. 920:227–232.

    Google Scholar 

  • Vogt, B. A., Crino, P. B., and Vogt, L. J. (1992). Recrganization of cinglulate cortex I Alzheimer’s disease: neuron loss, neuritic plaques, and muscarinic receptor binding. Cereb. Cortex 2:526–535.

    PubMed  Google Scholar 

  • Wei, W., Norton, D.D., Wang, X., and Kusiak, J.W. (2002). AΒ 17–42 in Alzheimer’s disease activates JNK and caspase-8 leading to neuronal apoptosis. Brain 125:2036–2043

    Article  PubMed  Google Scholar 

  • West, M. J. (1994).Differences in the pattern of hippocampal neuron loss in normal ageing andAlzheimer’s disease. Lancet 344:526–535.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yong K. Kim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lim, H.J., Cho, J.S., Oh, J.H. et al. NSE-Controlled Carboxyl-Terminus of APP Gene Over-Expressing in Transgenic Mice Induces Altered Expressions in Behavior, Aβ-42, and GSK3β Binding Proteins. Cell Mol Neurobiol 25, 833–850 (2005). https://doi.org/10.1007/s10571-005-4937-7

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-005-4937-7

Keywords

Navigation