Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin
| Autor: | Rae Kyung Christina Lee, Tomohiro Morio, Laurie H. Glimcher, Eunji Cheong, Seung-Hyung Kim, Fumiko Honda, Jong Soon Lim, Nae Hyun Lee, Yoon Chul Shin, Inhee Mook-Jung, Jae-Hyuck Shim, Sang Kyou Lee, Won Ki Kim, Tae Yoon Park |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Programmed cell death
Cytoplasm Amyloid beta Green Fluorescent Proteins Pharmaceutical Science Inflammation Apoptosis Mice Transgenic Biology Pharmacology Neuroprotection Mice Cell Line Tumor medicine Animals Humans Humanin Neurons Cell Death Caspase 3 Neurodegeneration Intracellular Signaling Peptides and Proteins Neurodegenerative Diseases medicine.disease Flow Cytometry Immunohistochemistry Rats Mice Inbred C57BL Disease Models Animal Neuroprotective Agents Animals Newborn Cytoprotection Immunology biology.protein Female medicine.symptom Intracellular |
| Zdroj: | Journal of controlled release : official journal of the Controlled Release Society. 166(3) |
| ISSN: | 1873-4995 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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