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miR-135a-5p 通过阿尔茨海默病小鼠模型中的 Rock2/Adducin1 信号通路介导记忆和突触损伤。

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

机构信息

Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.

出版信息

Nat Commun. 2021 Mar 26;12(1):1903. doi: 10.1038/s41467-021-22196-y.

DOI:10.1038/s41467-021-22196-y
PMID:33771994
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7998005/
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.

摘要

异常的 microRNAs（miRNAs）调节与阿尔茨海默病（AD）的发病机制有关，但在 AD 中发现的大多数异常表达的 miRNAs 不受突触活动调节。在这里，我们报告 miR-135a-5p/Rock2/Add1 的功能障碍导致 AD 小鼠模型中的记忆/突触紊乱。AD 模型小鼠兴奋性海马神经元中的 miR-135a-5p 水平显著降低。这种减少依赖于 tau 并由 Foxd3 介导。抑制 miR-135a-5p 导致突触紊乱和记忆损伤。此外，由于 miR-135a-5p 的缺失导致 Rock2 水平升高，通过磷酸化 Add1 上的 Ser726 在 AD 的突触紊乱中发挥重要作用。用膜通透肽阻断 Add1 上 Ser726 的磷酸化可有效挽救 AD 小鼠的记忆损伤。总之，这些发现表明，与突触相关的 miR-135a-5p 通过 Rock2/Add1 信号通路介导 AD 中的突触/记忆缺陷，为 AD 提供了一种潜在的治疗策略。

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