Treatment of NP106-expressing adeno-associated virus in microglia-mediated Aβ clearance and behavioral deficits in APP/PS1 mice

Aβ plays an important role in the pathogenesis of Alzheimer’s disease (AD), and passive immunotherapy targeting Aβ has emerged as a promising treatment approach. However, the administration of antibody drugs is limited due to many concerns. Therefore, using adeno-associated virus (AAV) gene therapy to deliver antibody drugs may introduce innovative treatment regimens for AD. We have previously shown that NP106, a novel anti-Aβ antibody, exhibits multiple therapeutic benefits for ameliorating brain Aβ burden and cognitive impairment in APP/PS1 mouse model of AD. In this study, we developed an NP106-expressing AAV (AAV-NP106) that can sustainably produce NP106 in vitro and in vivo. Data showed that NP106 from AAV-NP106-infected primary cultures was similar to NP106 regularly generated by CHO cells, showing comparable Aβ binding affinity and neuroprotection against Aβ toxicity. After a single intracerebroventricular administration of AAV-NP106, various brain regions of APP/PS1 mice exhibited the presence of NP106, co-localized with Aβ plaques. The data also indicated that AAV-NP106 treatment significantly reduced brain Aβ burden and improved cognitive deficits in APP/PS1 mice compared to controls. Findings further showed that the therapeutic potential of AAV-NP106 may be due to enhanced microglia-mediated Aβ phagocytosis and an increase in the number of Aβ plaques-associated microglia that displayed a branched and ramified morphology, accompanied by changes in CD68 levels. These results suggest that AAV-NP106 treatment rejuvenates microglial functioning without triggering microglial overactivation, while mitigating Aβ pathology and behavioral deficit in APP/PS1 mice. Therefore, AAV-NP106 might confer a novel approach for the treatment of AD.