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Brain‐Wide Neuroregenerative Gene Therapy Improves Cognition in a Mouse Model of Alzheimer's Disease
https://orcid.org/0000-0002-3816-8891
AbstractAlzheimer's disease (AD) is a progressive and irreversible brain disorder with extensive neuronal loss in the neocortex and hippocampus. Current therapeutic interventions focus on the early stage of AD but lack effective treatment for the late stage of AD, largely due to the inability to replenish the lost neurons and repair the broken neural circuits. In this study, by using engineered adeno‐associated virus vectors that efficiently cross the blood–brain‐barrier in the mouse brain, a brain‐wide neuroregenerative gene therapy is developed to directly convert endogenous astrocytes into functional neurons in a mouse model of AD. It is found that ≈500 000 new neurons are regenerated and widely distributed in the cerebral cortex and hippocampus. Importantly, it is demonstrated that the converted neurons can integrate into pre‐existing neural networks and improve various cognitive performances in AD mice. Chemogenetic inhibition of the converted neurons abolishes memory enhancement in AD mice, suggesting a pivotal role for the newly converted neurons in cognitive restoration. Together, brain‐wide neuroregenerative gene therapy may provide a viable strategy for the treatment of AD and other brain disorders associated with massive neuronal loss.
Brain‐Wide Neuroregenerative Gene Therapy Improves Cognition in a Mouse Model of Alzheimer's Disease
https://orcid.org/0000-0002-3816-8891
AbstractAlzheimer's disease (AD) is a progressive and irreversible brain disorder with extensive neuronal loss in the neocortex and hippocampus. Current therapeutic interventions focus on the early stage of AD but lack effective treatment for the late stage of AD, largely due to the inability to replenish the lost neurons and repair the broken neural circuits. In this study, by using engineered adeno‐associated virus vectors that efficiently cross the blood–brain‐barrier in the mouse brain, a brain‐wide neuroregenerative gene therapy is developed to directly convert endogenous astrocytes into functional neurons in a mouse model of AD. It is found that ≈500 000 new neurons are regenerated and widely distributed in the cerebral cortex and hippocampus. Importantly, it is demonstrated that the converted neurons can integrate into pre‐existing neural networks and improve various cognitive performances in AD mice. Chemogenetic inhibition of the converted neurons abolishes memory enhancement in AD mice, suggesting a pivotal role for the newly converted neurons in cognitive restoration. Together, brain‐wide neuroregenerative gene therapy may provide a viable strategy for the treatment of AD and other brain disorders associated with massive neuronal loss.
Brain‐Wide Neuroregenerative Gene Therapy Improves Cognition in a Mouse Model of Alzheimer's Disease
https://orcid.org/0000-0002-3816-8891
AbstractAlzheimer's disease (AD) is a progressive and irreversible brain disorder with extensive neuronal loss in the neocortex and hippocampus. Current therapeutic interventions focus on the early stage of AD but lack effective treatment for the late stage of AD, largely due to the inability to replenish the lost neurons and repair the broken neural circuits. In this study, by using engineered adeno‐associated virus vectors that efficiently cross the blood–brain‐barrier in the mouse brain, a brain‐wide neuroregenerative gene therapy is developed to directly convert endogenous astrocytes into functional neurons in a mouse model of AD. It is found that ≈500 000 new neurons are regenerated and widely distributed in the cerebral cortex and hippocampus. Importantly, it is demonstrated that the converted neurons can integrate into pre‐existing neural networks and improve various cognitive performances in AD mice. Chemogenetic inhibition of the converted neurons abolishes memory enhancement in AD mice, suggesting a pivotal role for the newly converted neurons in cognitive restoration. Together, brain‐wide neuroregenerative gene therapy may provide a viable strategy for the treatment of AD and other brain disorders associated with massive neuronal loss.
Brain‐Wide Neuroregenerative Gene Therapy Improves Cognition in a Mouse Model of Alzheimer's Disease
Advanced Science
Wu, Zheng (author) / Xu, Liang (author) / Xie, Yu (author) / Sambangi, Abhijeet (author) / Swaminathan, Shreya (author) / Pei, Zifei (author) / Ji, Wenyu (author) / Li, Zeru (author) / Guo, Yaowei (author) / Li, Zhifei (author)
2025-02-14
Article (Journal)
Electronic Resource
English
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