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

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Neurodegenerative Diseases
Alzheimer Disease
Cell Death
Caspase 3
Apoptosis Regulatory Proteins
Middle Cerebral Artery Infarction
Therapeutics
Blood-Brain Barrier
Amyloid
Brain Injuries
Disease Progression
humanin
Cytoplasm
Animal Models
Stroke
Apoptosis
Brain
Pharmaceutical Preparations
Inhibition (Psychology)

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Park, Tae Yoon ; Kim, Seung Hyung ; Shin, Yoon Chul ; Lee, Nae Hyun ; Lee, Rae Kyung Christina ; Shim, Jae Hyuck ; Glimcher, Laurie H. ; Mook-Jung, Inhee ; Cheong, Eunji ; Kim, Won Ki ; Honda, Fumiko ; Morio, Tomohiro ; Lim, Jong Soon ; Lee, Sang Kyou. / Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin. In: Journal of Controlled Release. 2013 ; Vol. 166, No. 3. pp. 307-315.
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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.",
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Park, TY, Kim, SH, Shin, YC, Lee, NH, Lee, RKC, Shim, JH, Glimcher, LH, Mook-Jung, I, Cheong, E, Kim, WK, Honda, F, Morio, T, Lim, JS & Lee, SK 2013, 'Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin', Journal of Controlled Release, vol. 166, no. 3, pp. 307-315. https://doi.org/10.1016/j.jconrel.2012.12.022

Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin. / Park, Tae Yoon; Kim, Seung Hyung; Shin, Yoon Chul; Lee, Nae Hyun; Lee, Rae Kyung Christina; Shim, Jae Hyuck; Glimcher, Laurie H.; Mook-Jung, Inhee; Cheong, Eunji; Kim, Won Ki; Honda, Fumiko; Morio, Tomohiro; Lim, Jong Soon; Lee, Sang Kyou.

In: Journal of Controlled Release, Vol. 166, No. 3, 28.03.2013, p. 307-315.

Research output: Contribution to journalArticle

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AU - Park, Tae Yoon

AU - Kim, Seung Hyung

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AU - Lee, Rae Kyung Christina

AU - Shim, Jae Hyuck

AU - Glimcher, Laurie H.

AU - Mook-Jung, Inhee

AU - Cheong, Eunji

AU - Kim, Won Ki

AU - Honda, Fumiko

AU - Morio, Tomohiro

AU - Lim, Jong Soon

AU - Lee, Sang Kyou

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N2 - 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.

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