Background: Compelling evidence has shown that long non-coding RNAs (lncRNAs) contribute to Alzheimer's disease (AD) pathogenesis including β-amyloid plaque deposition (Aβ) and intracellular neurofibrillary tangles. In this study, we aimed to investigate the critical role of lncRNA Gm20063 in AD.
Method: Six-month-old male APP/PS1 transgenic mice and wild type (WT) C57BL/6 (B6) littermates were obtained from the Nanjing University Animal Model Research Center. AAV mediated over-expression or knockdown of Gm20063 in hippocampus neurons though stereotactic technique. Behavioral tests were performed to evaluate the cognitive and memory function of APP/PS1. Electrophysiological tests, Golgi staining and Western blotting was applied to determine the synaptic plasticity. The potential targets of Gm20063 were identified by mass spectrometry (MS), RNA-binding protein immunoprecipitation (RIP) and RNA in situ hybridization (RNA scope).
Result: The expression of Gm20063 was significantly increased in the hippocampus of APP/PS1 mice. Overexpression of Gm20063 ameliorated cognitive decline, reduced Aβ deposition, enhanced synaptic plasticity and Aβ phagocytized by microglia in APP/PS1. In addition, knockdown of Gm20063 accelerated the memory deficits and worsened the AD pahogenesis in APP/PS1 mice. Furthermore, Gm20063 interacted with TDP-43 in the hippocampus, and regulated the post-translational modifications of TDP-43.
Conclusion: Gm20063 attenuated cognitive decline in AD mice, and targeting Gm20063 might be an effective therapy for AD treatment.
© 2024 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.