title: In vivo AAV1 transduction with hRheb(S16H) protects hippocampal neurons by BDNF production.
abstract: Recent evidence has shown that Ras homolog enriched in brain (Rheb) is dysregulated in Alzheimer's disease (AD) brains. However, it is still unclear whether Rheb activation contributes to the survival and protection of hippocampal neurons in the adult brain. To assess the effects of active Rheb in hippocampal neurons in vivo, we transfected neurons in the cornu ammonis 1 (CA1) region in normal adult rats with an adeno-associated virus containing the constitutively active human Rheb (hRheb(S16H)) and evaluated the effects on thrombin-induced neurotoxicity. Transduction with hRheb(S16H) significantly induced neurotrophic effects in hippocampal neurons through activation of mammalian target of rapamycin complex 1 (mTORC1) without side effects such as long-term potentiation impairment and seizures from the alteration of cytoarchitecture, and the expression of hRheb(S16H) prevented thrombin-induced neurodegeneration in vivo, an effect that was diminished by treatment with specific neutralizing antibodies against brain-derived neurotrophic factor (BDNF). In addition, our results showed that the basal mTORC1 activity might be insufficient to mediate the level of BDNF expression, but hRheb(S16H)-activated mTORC1 stimulated BDNF production in hippocampal neurons. These results suggest that viral vector transduction with hRheb(S16H) may have therapeutic value in the treatment of neurodegenerative diseases such as AD.
authors.affiliation: 1] School of Life Sciences, Kyungpook National University, Daegu, Korea [2] BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea.
authors.forename: Min-Tae
authors.initials: MT
authors.lastname: Jeon
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea [2] Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Jin Han
authors.initials: JH
authors.lastname: Nam
authors.affiliation: Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Korea.
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Shin
authors.affiliation: 1] School of Life Sciences, Kyungpook National University, Daegu, Korea [2] BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea.
authors.forename: Eunju
authors.initials: E
authors.lastname: Leem
authors.affiliation: 1] School of Life Sciences, Kyungpook National University, Daegu, Korea [2] BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea.
authors.forename: Kyoung Hoon
authors.initials: KH
authors.lastname: Jeong
authors.affiliation: Center for Food and Nutritional Genomics Research, Kyungpook National University, Daegu, Korea.
authors.forename: Un Ju
authors.initials: UJ
authors.lastname: Jung
authors.affiliation: 1] School of Life Sciences, Kyungpook National University, Daegu, Korea [2] BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea.
authors.forename: Young-Seuk
authors.initials: YS
authors.lastname: Bae
authors.affiliation: Department of Physiology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Jin
authors.affiliation: Department of Neurology, Columbia University, New York, New York, USA.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kholodilov
authors.affiliation: 1] Department of Neurology, Columbia University, New York, New York, USA [2] Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Burke
authors.affiliation: 1] Cancer Preventive Material Development Research Center, Department of Science, College of Korean Medicine, Kyung Hee University, Seoul, Korea [2] Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, Seoul, Korea.
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea [2] Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Byung Kwan
authors.initials: BK
authors.lastname: Jin
authors.affiliation: 1] School of Life Sciences, Kyungpook National University, Daegu, Korea [2] BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea [3] Institute of Life Science and Biotechnology, Kyungpook National University, Daegu, Korea [4] Brain Science and Engineering Institute, Kyungpook National University, Daegu, Korea.
authors.forename: Sang Ryong
authors.initials: SR
authors.lastname: Kim
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000633:toxicity; D014161:Transduction, Genetic / Q000379:methods*
chemical_list: D057134:Antibodies, Neutralizing; D019208:Brain-Derived Neurotrophic Factor; D046912:Multiprotein Complexes; D009479:Neuropeptides; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D013917:Thrombin; D020559:Monomeric GTP-Binding Proteins