Nurr1 and Foxa2 Delivered by Adeno‐Associated Virus 9 Ameliorate the Pathologies and Symptoms of Alzheimer’s Disease Models

Abstract

AbstractBackgroundSince conventional chemical drugs or proteins have not shown sufficient clinical benefits for cognitive impairments in Alzheimer’s disease (AD), we could try to develop novel therapeutic interventions for AD such as gene therapy. In this study, we evaluated a novel therapeutic modality of AAV9 vectors expressing Nurr1 and Foxa2 genes to treat AD symptoms and pathologies in animal disease models.MethodThe AAV9 vectors expression Nurr1 and Foxa2 were injected together into the hippocampi and lateral ventricles of two different AD models, such as 3x Transgenic (15‐18 months) and 5x Familial Alzheimer Disease (3 months) mice. We tested memory and cognitive functions, accumulation of amyloid β and Tau protein, inflammation and immune activity in the brain of AD models.ResultCombined transduction of AAV9‐Nurr1 and AAV9‐Foxa2 remarkably improved memory and cognitive functions of 3xTg mice in Y‐maze and water‐maze tests compared to vehicle‐treated group. In 5xFAD mice, Nurr1 and Foxa2 co‐expression effectively rescued memory deficits in the passive avoidance and novel object recognition tests, and made the impaired long‐term potentiation restore to wild‐type level.We intensively investigated modes of action of therapeutic genes. Nurr1 and Foxa2 co‐expression significantly decreased Aβ deposits in the brain of 3xTg and 5xFAD mice. Subsequent transcriptome analyses revealed that two genes up‐regulated the expression of Aβ‐degrading enzymes.Tau plaque formation was also reduced in therapeutic gene‐treated 3xTg group, accompanied by deceased phosphorylation of Tau through inflammasome suppression and GSK‐3β inactivation.Nurr1 and Foxa2 ameliorated neuro‐toxic environment by correcting pathologic inflammatory glial phenotypes. They decreased the expression of inflammatory cytokines, chemokines, and complements through inactivation of NF‐κB pathway, while up‐regulated expression of neurotrophic factors.Along with increased expression of pre‐ and post‐synaptic markers, synaptic density in the hippocampal CA1 was greater in the 3xTg mice treated with therapeutic genes than control.ConclusionA series of functional, histologic and transcriptome analyses revealed that the co‐expression of Nurr1 and Foxa2 attenuated AD‐associated Aβ and Tau proteinopathy, neuro‐inflammation, immune activation, and synaptic loss in multiple in vitro and in vivo AD models. These findings collectively indicate intra‐cranial delivery of Nurr1 and Foxa2 using AAV9 could be an efficient disease‐modifying therapy for AD.