한빛사 논문
Yunseon Yang1,2,10, Min-Jong Seok1,2,10, Ye Eun Kim3,4,10, Yunjung Choi5,10, Jae-Jin Song1,2,10, Yanuar Alan Sulistio1,2, Seong-hoon Kim1,2, Mi-Yoon Chang1,2, Soo-Jin Oh6, Min-Ho Nam6, Yun Kyung Kim5,7, Tae-Gyun Kim8, Heh-In Im5,7,*, Seong-Ho Koh3,* and Sang-Hun Lee1,2,9,*
1Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea. 2Hanyang Biomedical Research Institute, Hanyang University, Seoul, Republic of Korea. 3Department of Neurology, Hanyang University Guri Hospital, Hangyang University College of Medicine, Guri, Republic of Korea. 4Graduate School of Translational Medicine, Hanyang University, Seoul, Republic of Korea. 5Convergence Research Center for Brain Science, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea. 6Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea. 7Division of Bio-Med, KIST School, Korea University of Science and Technology, Seoul, Republic of Korea. 8Innopeutics Corporation, Seoul, Republic of Korea. 9Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Republic of Korea. 10These authors contributed equally: Yunseon Yang, Min-Jong Seok, Ye Eun Kim, Yunjung Choi, Jae-Jin Song.
*Corresponding author.
Abstract
There is a compelling need to develop disease-modifying therapies for Alzheimer’s disease (AD), the most common neuro-degenerative disorder. Together with recent progress in vector development for efficiently targeting the central nervous system, gene therapy has been suggested as a potential therapeutic modality to overcome the limited delivery of conventional types of drugs to and within the damaged brain. In addition, given increasing evidence of the strong link between glia and AD pathophysiology, therapeutic targets have been moving toward those addressing glial cell pathology. Nurr1 and Foxa2 are transcription/epigenetic regulators that have been reported to cooperatively regulate inflammatory and neurotrophic response in glial cells. In this study, we tested the therapeutic potential of Nurr1 and Foxa2 gene delivery to treat AD symptoms and pathologies. A series of functional, histologic, and transcriptome analyses revealed that the combined expression of Nurr1 and Foxa2 substantially ameliorated AD-associated amyloid β and Tau proteinopathy, cell senescence, synaptic loss, and neuro-inflammation in multiple in vitro and in vivo AD models. Intra-cranial delivery of Nurr1 and Foxa2 genes using adeno-associated virus (AAV) serotype 9 improved the memory and cognitive function of AD model mice. The therapeutic benefits of gene delivery were attained mainly by correcting pathologic glial function. These findings collectively indicate that AAV9-mediated Nurr1 and Foxa2 gene transfer could be an effective disease-modifying therapy for AD.
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