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. 2005 Aug;25(5):881–898. doi: 10.1007/s10571-005-4950-x

Early Changes in Behavior Deficits, Amyloid β-42 Deposits and MAPK Activation in Doubly Transgenic Mice Co-expressing NSE-Controlled Human Mutant PS2 and APPsw

Dae Y Hwang 1, Jung S Cho 1, Jae H Oh 1, Sun B Shim 1, Seung W Jee 1, Su H Lee 1, Su J Seo 1, Chi W Song 2, Seok H Lee 3, Yong K Kim 1,✉
PMCID: PMC11529551  PMID: 16133940

Abstract

  1. Doubly transgenic mice were some differences in the period proceeding of the development of Aβ-42 deposits and behavioral deficits. It was not characterized human mutant PS2 (hPS2) with APPsw in the brains of double transgenic mice. The aim of this study was to examine whether doubly transgenic mice co-expressing NSE-controlled APPsw and hPS2m develop AD-like phenotypes much earlier than singly APPsw or hPS2m alone.

  2. We produced doubly transgenic mice from a cross between our previously created NSE-controlled hPS2m and an APPsw transgenic line. This doubly transgenic line was quantitatively produced by cross with age-matched control mice, and the produced mice were separated into 5, 6, 7 and 8-month old age groups. At the age of 8 months, the four groups of mice were tested for behavioral function, levels of Aβ-42 deposition, and potential signaling events.

  3. It was shown that all the AD-like phenotypes, including behavior deficits, Aβ-42 levels, MAPK activation and ER expressions in doubly transgenic mice develop much earlier in the early time of AD development than their singly transgenic and non-transgenic littermates.

  4. The results suggest that elevated Aβ-42 levels, and MAPK activation in doubly transgenic mice are model for early diagnosis and treatment of AD with therapeutic drug.

Keywords: alzheimer, MAPK, transgenic, APPsw, PS2

References

  1. 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. Celeb. Cortex. 1:103–106. [DOI] [PubMed] [Google Scholar]
  2. Atkins, C. M., Selker, J. C., Petratis, J. J., Trzzascos, J. M., and Sweat, J. D. (1998). The MAPK cascade is required for mammalian associative learning. Nat. Neurosci. 1:602–609. [DOI] [PubMed] [Google Scholar]
  3. Bard, F., Cannon, C., 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., Nguyen, 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. [DOI] [PubMed] [Google Scholar]
  4. Borchelt, D. R., Ratovitski, T., van Lare, J., Lee, M. K., Gonzales, V., Jenkins, N. A., Copeland, N. G., Price, D. L., and Sisodia, S. S. (1997). Accreted amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron19:939–945. [DOI] [PubMed] [Google Scholar]
  5. Forss-Petter, S., Danielson, P. E., Catsicas, S., Battenberg, E., Price, J., Nerenberg, M., and Sutcliffe, J. G. (1990). Transgenic mice expressing beta-galactosidase in mature neurons under neuron-specific enolase promoter control. Neuron5:187–197. [DOI] [PubMed] [Google Scholar]
  6. Gordon, M. N., King, D. L., Diamond, D. M., Jantzen, P. T., Boyett, K. V., Hope, C. E., Hatcher, J. M., DiCarlo, G., Gottechall, W. P .E., Morgan, D., and Aredash, G. W. (2001). Correlation between cognitive deficits and Aβ deposits in transgenic APP+PS1 mice. Neurobiol. Aging22:377–385. [DOI] [PubMed] [Google Scholar]
  7. Haass, C., and Stroper, B. (1999). The presenilin in Alzheimer’s disease-proteolysis hold the key. Science286:916–919. [DOI] [PubMed] [Google Scholar]
  8. Holcomb, L., Gordon, M. N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Muller, R., Morgan, D., Sanders, S., Zehr, C., O’Campo, K., Hardy, J., Prada, C.-M., Eckman, C., Younkin, S., Hsiao, K., and Duff, K. (1998). Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med. 4:97–100. [DOI] [PubMed] [Google Scholar]
  9. 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. K., 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. [DOI] [PubMed] [Google Scholar]
  10. 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 expression of pathogenic phenotype in Alzheimer’s diseased transgenic mice carrying NSE-controlled APPsw. Exp. Neurol. 186:20–32. [DOI] [PubMed] [Google Scholar]
  11. Irizarry, M. C., Soriana, F., McNamara, M., Page, K. J., Schenk, D., Games, D., and Hyman, B. T. (1997a). Aβ deposition is associated with neuropil changes, but not with overt neuronalloss in the human amyloid precursor protein V717F (PDAPP) transgenic mice. J. Neurosci. 17:7053–7059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Irizarry, M. C., McNarama, M., Fedorchak, K., Hsiao, K., and Hyman, B. T. (1997b). APPsw transgenic mice develop age-related A beta deposits and neurophil abnormalities, but no neuronal loss CA1. J. Neurophathol. Exp. Neurol. 56:965–973. [DOI] [PubMed] [Google Scholar]
  13. Kuo, Y. M., Emmerling, M. R., Vigo-Pelfrey, C., Kasunic, T. C., Kirkpatrick, J. B., Murdoch, G. H., Ball, M. J., and Roher, A. E. (1996). Water-soluble Aβ (N-40, N-42) oligomers in normal and Alzheimer disease brains. J. Biol. Chem. 271:4077–4081. [DOI] [PubMed] [Google Scholar]
  14. Leu, L. F., Kuo, Y. M., Roher, A. E., Brachova, L., Sue, L., Beach, T., Kurth, J. H., Rydel, R. E., and Rogers, J. (1999). Soluble amyloid β peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am. J. Pathol. 155:853–862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. McLean, C. A., Cherny, R. A., Fraser, F. W., Fuller, S. J., Smith, M. J., Beyreuther, K., Bush, A. I., and Master, C. L. (1999). Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neurl. 46:860–866. [DOI] [PubMed] [Google Scholar]
  16. Moechars, D., Dewatcher, L., Lorent, K., Reverse, D., Baekelandt, V., Naidu, A., Tesseur, I., Spittaels, K., Van Den Haute, C., Cordell, B., Checler, F., Godaux, E., and van leuven, F. (1999). Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J. Biol. Chem. 274:6483–6492. [DOI] [PubMed] [Google Scholar]
  17. Morris, R. G. M., Garrud, P., Rawlins, J. N. P., and O’Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature297:681–683. [DOI] [PubMed] [Google Scholar]
  18. Naslund, J., Haroutunian, V., Moshs, R., Davis, K. L., Davies, P., Greengard, P., and Buxbaum, J. D. (2000). Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline. J. Am. Med. Assoc. 283:1571–1577. [DOI] [PubMed] [Google Scholar]
  19. Oyama, F., Sawamura, N., Kobayashi, K., Morishima-Kawashima, M., Kuramuchi, T., Ito, M., Tomita, T., Maruyama, K., Saido, T. C., Iwatsubo, T., Capell, A., Walter, J., Grunberg, J., Ueyama, Y., Haass, C., Ihara, Y. (1998). Mutant presenilin 2 transgenic mouse: Effect on an age-dependent increase of amyloid β-protein 42 in the brain. J. Neurochem. 71:313–322. [DOI] [PubMed] [Google Scholar]
  20. Savage, M. J., Lin, Y. G., Ciallella, J. R., Flood, D. G., and Scott, R. W. (2002). Activation of c-Jun N-terminal kinase and p38 in an Alzheimer’s disease model is associated with amyloid deposition. J. Neurosci. 22:3376–3385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sawamura, N., Morishima-Kawashima, M., Waki, H., Kobayashi, K., Kuramochi, T., Frosch, M. P., Ding, K., Ito, M., Kim, T. W., Tanzi, R. E., Oyama, F., Tabila, T., Ando, S., and Ihara, Y. (2000). Mutant presenilin 2 transgenic mice. A large increase in the levels of Aβ-42 presumably associated with the low density membrane domain that contains decreased levels of glycerophospholipids and sphingomyelin. J. Biol. Chem. 275:27901–27908. [DOI] [PubMed] [Google Scholar]
  22. Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Hung, J., Johnson-Wood, K., Jhan, K., Kholodenko, D., Lee, M., Liao, Z., Kieberburg, I., Matter, R., Mutter, L., Soriano, F., Shopp, G., Vasquenz, N., Vandevert, C., Walker, S., Wogulis, M., Yednock, T., Games, D., and Seubert, P. (1999). Immunization with amyloid β attenuates Alzheimer’s disease-like pathology in the PDAPP mouse. Nature400:173–177. [DOI] [PubMed] [Google Scholar]
  23. Shoji, M., Iwakami, N., Takeuchi, S., Waragai, M., Suzuki, M., Kanazawa, I., Lippa, C. F., Ono, S., and Okazawa, H. (2000). JNK activation is associated with intracellular β-amyloid accumulation. Mol. Brain Res. 85:221–233. [DOI] [PubMed] [Google Scholar]
  24. Suzuki, N., Cheung, T. T., Cai, X. D., Odaka, A., Otvos, L. Jr., Eckman, C., Golde, T. E., and Younkin, S. G. (1994). An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science264:1336–1440. [DOI] [PubMed] [Google Scholar]
  25. Takeuchi, A., Irizarry, M. C., Duff, K., Saido, T. C., Hsiao Ashe, K., Hasegawa, M., Man, D. M. A., Hyman, B. T., and Iwtsubo, T. (2000). Age-related amyloid β deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid β precursor protein Swedish mutant is not associated with global neuronal loss. Am. J. Pathol. 157:331–339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Tomita, T., Maruyama, K., Saito, T. C., Kume, H., Shinozaki, K., Tokuriro, S., Capell, A., Walter, J., Grunberg, J., Haass, C., Iwatsubo, T., and Obata, K. (1997). The preselin 2 mutation (N141I) linked to familiar Alzheimer disease (Volga German Families) increases the secretion of amyloid β-protein ending at the 42nd (or 43rd residue. Proc. Natl. Acad. Sci. USA. 94:2025–2030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Troy, C. M., Rabacchi, S. A., Xu, Z., Maroney, A. C., Connors, T. J., Shelanski, M. L., and Greene, L. A. (2001). β-amyloid—induced neuronal apoptosis requires c-Jun N-terminal kinase activation. J. Neurochem. 77:157–164. [DOI] [PubMed] [Google Scholar]
  28. Tsien, J. Z., Huerta, P. T., and Tonegawa, S. (1996). The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell87:1327–1338. [DOI] [PubMed] [Google Scholar]
  29. van de Craen, M., de Jonghe, C., van den Brande, I., Declercq, W., van Gassen, G., van Criekinge, W., Van derhoeven, I., Fiers, W., van Broeckhoeven, C., Hendriks, L., and Van denabeele, P. (1999). Identification of caspases that cleave presenilin-1 and presenilin-2. Five presenilin-1 mutations do not alter the sensitivity of PS1 to caspases. FEBS Lett. 445:149–154. [DOI] [PubMed] [Google Scholar]
  30. Vogt, B. A., Crino, P. B., and Vogt, L. J. (1992). Reorganization of cingulate cortex I Alzheimer’s disease: Neuron loss, neurite plaques, and muscarinic receptor binding. Cereb. Cortex. 2:526–535. [DOI] [PubMed] [Google Scholar]
  31. Wang, J., Dickson, D. W., Trojanoweski, J. Q., and Lee, V. M. (1999). The level of soluble versus insoluble brain Aβ distinguishes Alzheimer’s disease from normal and pathologic aging. Exp. Neurol. 158:328–337. [DOI] [PubMed] [Google Scholar]
  32. West, M. J., Coleman, P. D., Flood, D. G., and Troncoso, J. C. (1994). Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’ disease. Lancet344:526–535. [DOI] [PubMed] [Google Scholar]
  33. Wong, T. P., Debeir, T., Duff, K., and Cuello, A. C. (1999). Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1 and amyloid precursor protein transgenes. J. Neurosci. 19:2706–2716. [DOI] [PMC free article] [PubMed] [Google Scholar]

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