Journal Club (July 5, 2021)

Nature Communications volume 12, Article number: 1903 (2021) Article Open Access
Published: 26 March 2021
miR-135a-5p mediates memory and synaptic impairments via the Rock2/Adducin1 signaling pathway in a mouse model of Alzheimer’s disease (miR-135a-5pは、アルツハイマー病のマウスモデルにおいて、Rock2 / Adducin1シグナル伝達経路を介して記憶とシナプス障害を仲介する)

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 & Ling-Qiang Zhu

The Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, P. R. 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

The Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, P. R. China

*華中科技大学 (ピンイン: Huázhōng kējì Dàxué)は、中華人民共和国湖北省武漢市洪山区にある大学である。

*Nature Communicationsは2010年よりNature Researchから発行されているオープンアクセスジャーナルである。



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.

アルツハイマー病(AD)の発症には、マイクロRNA(miRNA)の異常な制御が関与していると考えられているが、ADで発見された異常な発現のmiRNAの多くは、シナプスの活動によって制御されていない。今回、私たちは、ADモデルマウスにおいて、miR-135a-5p/Rock2/Add1の機能障害が記憶・シナプス障害を引き起こすことを報告した。miR-135a-5pレベルは、ADモデルマウスの興奮性海馬ニューロンで有意に減少していた。この減少はタウ依存性であり、Foxd3が介在している。miR-135a-5pを阻害すると、シナプス障害や記憶障害が生じる。さらに、miR-135a-5pの欠損によるRock2の過剰な発現は、adducin 1 (Add1)のSer726のリン酸化を介して、ADのシナプス障害に重要な役割を果たしている。このAdd1上のSer726のリン酸化を膜透過性のペプチドでブロックすると、ADマウスの記憶障害が効果的に回復する。以上の結果から、シナプス関連のmiR-135a-5pがRock2/Add1シグナル伝達経路を介してADのシナプス/記憶障害を引き起こすことが明らかになり、ADの治療戦略の可能性が示された。

ab Fold changes of synaptic activity associated with microRNAs (miRNAs) in the hippocampus of 12-month-old (a) or 9-month-old (b) APP/PS1 and control mice (WT) (n = 4 for each group). c Relative expression of miR-135a-5p in the hippocampus of APP/PS1 and control mice (WT) at different months as indicated (n = 4 for each group, two-way ANOVA, p < 0.0001). d The distribution of miR-135a-5p in glutamatergic excitatory neurons in hippocampal slices of 9 months APP/PS1 and control mice (WT) by co-immunofluorescence experiments with the antibody of CamKII (Green) and FISH of miR-135a-5p (Red). The amplification images were shown at the bottom of each group. Scale bar = 20 μm (upper), 5 μm (lower) (n = 3 for each group). e Quantification of fluorescence intensity for miR-135a-5p in CaMKII positive neurons from (d) (n = 11, 17 for WT, APP/PS1, p < 0.0001). f qRT-PCR was used to evaluate the expression of miR-135a-5p in the primary culture neurons at DIV 10 after overexpression of AAV-hTau (Tau) or control virus (Con) for 72 h (n = 3 for each group). g A representative immunofluorescence staining of FISH for miR-135a-5p (Red) and immunofluorescence experiments with the antibody of Tau-5 (Tau, Green) in hippocampus of 9 months APP/PS1 mice. Scale bar = 20 μm (left), 5 μm (right). h The fluorescence correlation of intensities of miR-135a-5p and Tau-5 in APP/PS1 mice as shown in panel (g) (n = 68 neurons from 5 mice). i The expression of miR-135a-5p in the frontal cortex from patients with AD and age-matched controls was measured by qRT-PCR (n = 4 for each group). (Data are presented as mean ± S.E.M. and two-tailed t tests were used unless otherwise specified. Source data are provided as a Source Data file. *p < 0.05, **p < 0.01, ***p < 0.001 vs. WT/Con).
Human brain disintegrating or breaking apart 3D rendering illustration. Memory impairments, neurological diseases like Parkinson’s or Alzheimer’s, amnesia, psychological and personality disorders and aging and senility concepts.



このサイトはスパムを低減するために Akismet を使っています。コメントデータの処理方法の詳細はこちらをご覧ください