microRNA-425 loss mediates amyloid plaque microenvironment heterogeneity and promotes neurodegenerative pathologies.
microRNA-425 loss mediates amyloid plaque microenvironment heterogeneity and promotes neurodegenerative pathologies.
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microRNA-425缺失介导淀粉样斑块微环境异质性并促进神经退行性病理。
DOI：
10.1111/acel.13454
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发表时间：
2021-10
期刊：
影响因子：
7.8
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Hu YB;Zhang YF;Ren RJ;Dammer EB;Xie XY;Chen SW;Huang Q;Huang WY;Zhang R;Chen HZ;Wang H;Wang G
Different cellular and molecular changes underlie the pathogenesis of Alzheimer's disease (AD). Among these, neuron‐specific dysregulation is a necessary event for accumulation of classic pathologies including amyloid plaques. Here, we show that AD‐associated pathophysiology including neuronal cell death, inflammatory signaling, and endolysosomal dysfunction is spatially colocalized to amyloid plaques in regions with abnormal microRNA‐425 (miR‐425) levels and this change leads to focal brain microenvironment heterogeneity, that is, an amyloid plaque‐associated microenvironment (APAM). APAM consists of multiple specific neurodegenerative signature pathologies associated with senile plaques that contribute to the heterogeneity and complexity of AD. Remarkably, miR‐425, a neuronal‐specific regulator decreased in AD brain, maintains a normal spatial transcriptome within brain neurons. We tested the hypothesis that miR‐425 loss correlates with enhanced levels of mRNA targets downstream, supporting APAM and AD progression. A miR‐425‐deficient mouse model has enhanced APP amyloidogenic processing, neuroinflammation, neuron loss, and cognitive impairment. In the APP/PS1 mouse model, intervening with miR‐425 supplementation ameliorated APAM changes and memory deficits. This study reveals a novel mechanism of dysregulation of spatial transcriptomic changes in AD brain, identifying a probable neuronal‐specific microRNA regulator capable of staving off amyloid pathogenesis. Moreover, our findings provide new insights for developing AD treatment strategies with miRNA oligonucleotide(s). The present study demonstrates that miR‐425 loss is responsible for PI3K‐Akt signaling suppression and impaired NPC proliferation. Moreover, miR‐425 loss induces dendritic spine defects and impaired synaptic plasticity. Taken together, miR‐425 loss following initial plaque deposition is the opening of the floodgates that mediates the ability of the APAM to cascade into a cellular phase of AD.
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DOI：
10.1186/alzrt265
发表时间：
2014
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Kitagishi Y;Nakanishi A;Ogura Y;Matsuda S
通讯作者：
Matsuda S
DOI：
10.1111/bpa.12133
发表时间：
2014-07
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
--
作者：
Hales CM;Dammer EB;Diner I;Yi H;Seyfried NT;Gearing M;Glass JD;Montine TJ;Levey AI;Lah JJ
通讯作者：
Lah JJ
影响因子：
18.3
作者：
Kreutzer AG;Nowick JS
通讯作者：
Nowick JS
DOI：
10.1073/pnas.0710263105
发表时间：
2008-04-29
影响因子：
11.1
作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
通讯作者：
De Strooper, Bart
影响因子：
25
作者：
Knafo, Shira;Sanchez-Puelles, Cristina;Esteban, Jose A.
通讯作者：
Esteban, Jose A.