miR-135a-5p mediates memory and synaptic impairments via the Rock2/Adducin1 signaling pathway in a mouse model of Alzheimer’s disease

Kai Zheng, Fan Hu, Yang Zhou, Juan Zhang, Jie Zheng, Chuan Lai, Wan Xiong, Ke Cui, Ya-Zhuo Hu, Zhi-Tao Han, Hong-Hong Zhang, Jian-Guo Chen, Heng-Ye Man, Dan Liu, Youming Lu () and Ling-Qiang Zhu ()
Additional contact information
Kai Zheng: Huazhong University of Science and Technology
Fan Hu: Huazhong University of Science and Technology
Yang Zhou: Huazhong University of Science and Technology
Juan Zhang: Huazhong University of Science and Technology
Jie Zheng: Huazhong University of Science and Technology
Chuan Lai: Huazhong University of Science and Technology
Wan Xiong: Huazhong University of Science and Technology
Ke Cui: Huazhong University of Science and Technology
Ya-Zhuo Hu: Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Disease, Institute of Geriatrics, Chinese PLA General Hospital and Chinese PLA Medical Academy
Zhi-Tao Han: Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Disease, Institute of Geriatrics, Chinese PLA General Hospital and Chinese PLA Medical Academy
Hong-Hong Zhang: Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Disease, Institute of Geriatrics, Chinese PLA General Hospital and Chinese PLA Medical Academy
Jian-Guo Chen: Huazhong University of Science and Technology
Heng-Ye Man: Boston University
Dan Liu: Huazhong University of Science and Technology
Youming Lu: Huazhong University of Science and Technology
Ling-Qiang Zhu: Huazhong University of Science and Technology

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer’s disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD.

Date: 2021
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DOI: 10.1038/s41467-021-22196-y

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