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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

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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Fig. 1
Fig. 2: Cell-type-specific effects of combined Nurr1 and Foxa2 expression.
Fig. 3: Memory and cognitive functions alleviated in AD mice treated with AAV9-Nurr1 + Foxa2.
Fig. 4: AD-associated Aβ, Tau pathologies, and synaptic loss ameliorated in AD mice treated with AAV9-Nurr1 + Foxa2.
Fig. 5: AAV9-based Nurr1 + Foxa2 gene delivery alleviated neuro-inflammation in AD mice.
Fig. 6: Transcriptome analyses suggesting potential therapeutic pathways induced by AAV9-Nurr1 + Foxa2 in 3 x Tg-AD mice.
Fig. 7: Glia-specific expression of Nurr1 + Foxa2 ameliorates AD-associated pathologies in an in vitro culture model.

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Acknowledgements

We thank YoungSoo Kim and Jisu Shin (Department of Pharmacy, Yonsei University) for the critical discussion and technical support.

Funding

This work was supported by the grants 2017R1A5A2015395 and 2020M3A9D8039925, funded by the National Research Foundation of Korea (NRF) of the Ministry of Science and ICT, Republic of Korea (to SHL), grants HI20C0253 and HU21C0113 from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (SHK).

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Performed research; YY, M-JS, J-JS, YEK, YC, S-hK, S-JO, and M-HN Designed research; S-HL, S-HK, H-II, M-YC, and T-GK. Analyzed data; YY, M-JS, J-JS, YEK, YC, YAS Wrote the paper; S-HL, YY, M-JS.

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Correspondence to Heh-In Im, Seong-Ho Koh or Sang-Hun Lee.

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Yang, Y., Seok, MJ., Kim, Y.E. et al. 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. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01693-6

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