Yang, Yunseon Seok, Min-Jong Kim, Ye Eun Choi, Yunjung Song, Jae-Jin Sulistio, Yanuar Alan Kim, Seong-hoon Chang, Mi-Yoon Oh, Soo-Jin Nam, Min-Ho Kim, Yun Kyung Kim, Tae-Gyun Im, Heh-In Koh, Seong-Ho Lee, Sang-Hun 2024-01-19T11:33:12Z 2024-01-19T11:33:12Z 2022-08-11 2023-12 1359-4184 https://pubs.kist.re.kr/handle/201004/114871 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 beta 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. English Nature Publishing Group Adeno-associated virus (AAV) 9-mediated gene delivery of Nurr1 and Foxa2 ameliorates symptoms and pathologies of Alzheimer disease model mice by suppressing neuro-inflammation and glial pathology Article 10.1038/s41380-022-01693-6 1 Molecular Psychiatry, v.28, no.12, pp.5359 - 5374 Molecular Psychiatry 28 12 5359 5374 N scie scopus 000832456900001 Biochemistry & Molecular Biology Neurosciences Psychiatry Biochemistry & Molecular Biology Neurosciences & Neurology Psychiatry Article NF-KAPPA-B AMYLOID-BETA A-BETA NUCLEAR RECEPTORS ASTROCYTES EXPRESSION MICROGLIA MEMORY NLRP3 ROLES