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

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.


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Male APP/PS1 mice of 4-month-old were purchased from the Jackson Laboratory (Bar Harbor, ME, NO. 034832). The male Tau-Knockout (Tau-/-) mouse of 6-month-old was generated using CRISPR-Cas9 system by specifically knocking out the sequence of exon 5 (Beijing Biocytogen Co., Ltd., Beijing, China). Adult male C57BL/6 mice of 6-month-old were purchased from the National Resource Center of Model Mice (Nanjing, China). In the behavioral experiment operation, gently touch the animal before catching them. If animals are killed, they will be dealt with at the Experimental Animal Central of Tongji Medical College, Huazhong University of Science and Technology.
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All the human participants are adult male and aged between 81-90 years old. Group of cortical tissues from the brains of nondementia control subjects and AD cases based on neuropathological diagnosis in figure 5F-I and supplementary figure 1H (4CON vs 4AD) was obtained from the Tissue Bank of the Institute of Geriatrics, Chinese PLA General Hospital and Chinese PLA Medical Academy.
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