4.8 Article

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

Journal

MOLECULAR PSYCHIATRY
Volume -, Issue -, Pages -

Publisher

SPRINGERNATURE
DOI: 10.1038/s41380-022-01693-6

Keywords

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Funding

  1. National Research Foundation of Korea (NRF) of the Ministry of Science and ICT, Republic of Korea [2017R1A5A2015395, 2020M3A9D8039925]
  2. Korea Health Technology R&D Project through the Korea Health Industry Development Institute - Ministry of Health & Welfare, Republic of Korea [HI20C0253, HU21C0113]
  3. National Research Foundation of Korea [2020M3A9D8039925] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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There is a need to develop disease-modifying therapies for Alzheimer's disease (AD) and gene therapy has been suggested as a potential treatment option. In this study, the researchers tested the therapeutic potential of delivering Nurr1 and Foxa2 genes to treat AD symptoms and pathologies. The results showed that the combined expression of Nurr1 and Foxa2 improved AD-associated amyloid beta and Tau proteinopathy, cell senescence, synaptic loss, and neuro-inflammation in multiple AD models. Intra-cranial delivery of these genes also improved memory and cognitive function in AD model mice. These findings suggest that AAV9-mediated Nurr1 and Foxa2 gene transfer could be an effective disease-modifying therapy for AD.
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.

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