Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin

Tae Yoon Park, Seung Hyung Kim, Yoon Chul Shin, Nae Hyun Lee, Rae Kyung Christina Lee, Jae Hyuck Shim, Laurie H. Glimcher, Inhee Mook-Jung, Eunji Cheong, Won Ki Kim, Fumiko Honda, Tomohiro Morio, Jong Soon Lim, Sang Kyou Lee

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Inhibition of the early intracellular event that triggers neurodegenerative cascades and reversal of neuronal cell death are essential for effective treatment of Alzheimer's disease (AD). In this study, a novel therapeutic for AD, a transducible humanin with an extended caspase-3 cleavage sequence (tHN-C3), was developed and showed multiple mechanisms of therapeutic action. These included targeted delivery of anti-apoptotic protein humanin through the blood-brain barrier (BBB) to neuronal cells, specific inhibition of caspase-3 activation to inhibit the early triggering of AD progression, and delivery of humanin into the cytoplasm of neuronal cells undergoing apoptosis where it exerts its anti-apoptotic functions effectively. The tHN-C3 prevented neuronal cell death induced by H2O2, or soluble Aβ42, via Bax binding. In animal models of AD induced by amyloid beta, in Tg2576 mice, and in the rat middle cerebral artery occlusion model of stroke, tHN-C3 effectively prevented neuronal cell death, inflammatory cell infiltration into the brain, and improved cognitive memory. The therapeutic effectiveness of tHN-C3 was comparable to that of Aricept, a clinically approved drug for AD treatment. Therefore, tHN-C3 may be a new remedy with multiple therapeutic functions targeting the early and late stages of neurodegeneration in AD and other brain injuries.

Original languageEnglish
Pages (from-to)307-315
Number of pages9
JournalJournal of Controlled Release
Volume166
Issue number3
DOIs
Publication statusPublished - 2013 Mar 28

Keywords

  • Alzheimer
  • Apoptosis
  • Drug delivery
  • Inflammation
  • Neuroprotection

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Park, T. Y., Kim, S. H., Shin, Y. C., Lee, N. H., Lee, R. K. C., Shim, J. H., Glimcher, L. H., Mook-Jung, I., Cheong, E., Kim, W. K., Honda, F., Morio, T., Lim, J. S., & Lee, S. K. (2013). Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin. Journal of Controlled Release, 166(3), 307-315. https://doi.org/10.1016/j.jconrel.2012.12.022