Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지

A Correspondence between Aging-related Reduction of Neprilysin and Elevation of Aβ-42 or γ-Secretase Activity in Transgenic Mice Expressing NSE-controlled APPsw or Human Mutant Presenilin-2

  • Lim Hwa-J. (College of Pharmacy, Ewha Womans University) ;
  • Kim Yong-K. (Division of Laboratory Animal Resources, Korea Food and Drug Administration, National Institute of Toxicological Research) ;
  • Sheen Yhun-Y. (College of Pharmacy, Ewha Womans University)
  • Published : 2006.06.01
Download PDF
⟨ Previous Next ⟩

Abstract

Neprilysin (Nep) is known to be important to degrade $A{\beta}$ derived from amyloid precursor protein (APP) by cleavage with $\beta-and\;\gamma$-secretases. In order to determine whether a correspondence between $A{\beta}-42/{\gamma}-secretase$ activity and Nep levels exists in postnatal aging of transgenic mice expressing either neuron-specific enolase (NSE)-controlled human mutant presenilin-2 (hPS2m) or APPsw alone, the levels of Nep expression and $A{\beta}-42/{\gamma}-secretase$ activity were examined age of 5, 12, and 20 months, respectively. The levels of Nep expression in both types of transgenic brains were decreased relative to those of control mice in a aging-related manner, while the level of $A{\beta}-42/{\gamma}-secretase$ activity was reversibly increased. Thus, changes in $A{\beta}-42$ may all reflect variation in amounts of Nep enzyme.

Keywords

References

  1. Akiyama, H., Kondo, H., Ikeda, K., Kato, M., and McGeer, P. L. (2001). Immunohistochemical localization of neprilysis in the human cerebral cortex: inverse association with vulnerability to amyloid $\beta$-protein (A$\beta$) deposition. Brain Res. 902, 277-281 https://doi.org/10.1016/S0006-8993(01)02390-3
  2. Apelt, J., Ach, K., and Schliebs, R. (2003). Aging-related downregulation of neprilysin, a putative $\beta$-amyloid-degrading enzyme, in transgenic Tg2576 Alzheimer-like mouse brain is accompanied by an astroglial upregulation in the vicinity of $\beta$-amyloid plaques. Neuroscu. Lett. 339, 183-186 https://doi.org/10.1016/S0304-3940(03)00030-2
  3. Glabe, C. (2000). Does Alzheimer disease tilt the scales of amyloid degradation versus accumulation? Nat. med. 6, 133-134 https://doi.org/10.1038/72215
  4. Gomez-Isla, T., Price, J. L., MaKeel, D. W., Morris, J. C., Growdon, J. H., and Hyman, B. T. (1996). Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci. 16, 4491-4500 https://doi.org/10.1523/JNEUROSCI.16-14-04491.1996
  5. 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 $\beta$-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer's disease. FASEB J. 16, 805-813 https://doi.org/10.1096/fj.01-0732com
  6. 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. K., Sheen, Y. Y., and Kim, Y. K. (2004). Aberrant expressions of pathogenic phenptype in Alzheimer's diseased transgenic mice carrying NSE-controlled APPsw. Exp. Neurol. 186, 20-3 https://doi.org/10.1016/j.expneurol.2003.09.021
  7. Iwata, N., Takaki, Y., Fukami, S., Tsubuki, S., and Saido, T. C. (2002). Region-specific reduction of A$\beta$-degrading endopeptidase, neprilysin, in mouse hippocampus upon aging. J. Neurosci. Res. 70, 493-500 https://doi.org/10.1002/jnr.10390
  8. Iwata, N., Tsubuki, S., Takaki, Y., Watanabe, K., Sekiguchi, M., Hosoli, E., Kawashima-Morishima, M., Lee, H. J., Hama, E., Sekine-Aizawa, Y., and Saido, T. C. (2000). Identification of the major A$\beta$-42 degrading catabolic pathway in brain parenchyma suppression leads to biochemical and pathological deposition. Nat. Med. 6, 143-150 https://doi.org/10.1038/72237
  9. Lu, B., Gerard, N. P., Kolakowski, L. F. Jr., Bozza, M., Zurakowski, D., Finco, O., Carroll, M. C., and Gerard, C. (1995). Neutral endopeptidase modulation of septic shock. J. Exp. Med. 181, 2271-2275 https://doi.org/10.1084/jem.181.6.2271
  10. Lu, B., Gerard, N. P., Kolakowski, L. F. Jr., Finco, O., Carroll, M. C., and Gerard, M. C. (1996). Neutral endopeptidase modulates septic shock. Ann. N.Y. Acad. Sci. 780, 156-163 https://doi.org/10.1111/j.1749-6632.1996.tb15119.x
  11. Mohajeri, M., Wollmer, M. A., and Nitsch, R. M. (2002). A$\beta$-42induced increase in neprilysin is associated with prevention of amyloid plaque formation in vivo. J. Biol. Chem. 277, 35460-35465 https://doi.org/10.1074/jbc.M202899200
  12. Tumer, A. J., Issac, R. E., and Coates, D. (2001). The neprilysin (NEP) family of zinc metalloendopeptidase genomics and function. Bioassays. 23, 261-269 https://doi.org/10.1002/1521-1878(200103)23:3<261::AID-BIES1036>3.0.CO;2-K
  13. Yasojima, K., Akiyama, H., McGeer, E. G., and McGeer, P. L. (2001a) Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship in deficient degradation of $\beta$amyloid peptide. Neurosci. Lett. 297, 97-100 https://doi.org/10.1016/S0304-3940(00)01675-X
  14. Yasojima, K., McGeer, E. G., and McGeer, P. L. (2001b). Relationship between $\beta$-amyloid peptide generating molecules and neprilysin in Alzheimer's disease and normal brain. Brain Res. 919, 115-121 https://doi.org/10.1016/S0006-8993(01)03008-6