title: Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin.
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.
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, National Creative Research Initiatives Center For Inflammatory Response Modulation, Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.
authors.forename: Tae-Yoon
authors.initials: TY
authors.lastname: Park
authors.forename: Seung-Hyung
authors.initials: SH
authors.lastname: Kim
authors.forename: Yoon-Chul
authors.initials: YC
authors.lastname: Shin
authors.forename: Nae-Hyun
authors.initials: NH
authors.lastname: Lee
authors.forename: Rae-Kyung Christina
authors.initials: RK
authors.lastname: Lee
authors.forename: Jae-Hyuck
authors.initials: JH
authors.lastname: Shim
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
authors.forename: Eunji
authors.initials: E
authors.lastname: Cheong
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Fumiko
authors.initials: F
authors.lastname: Honda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.forename: Jong-Soon
authors.initials: JS
authors.lastname: Lim
authors.forename: Sang-Kyou
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D019610:Cytoprotection; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; C485184:enhanced green fluorescent protein; C427211:humanin; D049452:Green Fluorescent Proteins; D053148:Caspase 3