A Novel MicroRNA-124/PTPN1 Signal Pathway Mediates Synaptic and Memory Deficits in Alzheimer’s Disease

Wang, Xiong; Liú, Dan; Huang, He-Zhou; Wang, Zhi-Hao; Hou, Tongyao; Yang, Xin; Pang, Pei; Wei, Na; Zhou, Yafan; Dupras, Marie-Josée; Calon, Frédéric; Wang, Yutian; Man, Heng‐Ye; Chen, Jianguo; Wang, Jian‐Zhi; Hébert, Sébastien; Lu, Youming; Zhu, Ling‐Qiang

doi:10.1016/j.biopsych.2017.07.023

Cited by 180 publications

(142 citation statements)

References 46 publications

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“…At DIV 9, anti‐MAP2 antibody was used to examine dendritic morphology. Compared to the scrambled peptide, 1 μM Aβ42 alone caused obvious impairments in the dendritic complexity at all points farther than 40 µm from the cell body when compared with scrambled peptide (Figure a–f), which is consistent with previous studies (Wang et al, ). Co‐application of melatonin or IIK7 effectively rescued the dendritic complexity damage caused by Aβ42 (Figure a–f).…”

Section: Resultssupporting

confidence: 91%

“…Next, we examined the exact underlying mechanisms of MT2’s protective effects against Aβ42‐induced dendritic injuries. Recently, the roles of microRNAs (miRNAs) in synaptic disorder observed in AD have been well elucidated (Li et al, ; Liu et al, ; Wang et al, ). Therefore, we then measured the expression of brain‐enriched miRNAs that had been reported previously upon the different treatments above.…”

Section: Resultsmentioning

confidence: 99%

“…As previously described (Wang et al, ), for mEPSCs recording, the cultured neurons were treated with Aβ (1 μM), Aβ plus melatonin (500 μM), Aβ plus IIK7 (10 μM) at DIV 7 for 2 days. The whole‐cell patch clamp recordings were performed at DIV 9.…”

Section: Methodsmentioning

confidence: 99%

“…Brain slices (300 μm) were used for fEPSP recording as previously described (Wang et al, ). Slices were pre‐incubated in oxygenated artificial CSF at 32°C for 1.5 hr, transferred to a recording chamber perfused constantly with artificial CSF.…”

Section: Methodsmentioning

confidence: 99%

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Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer’s disease via C/EBPα/miR‐125b pathway

Tang

Wang

et al. 2019

Aging Cell

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Impairments of dendritic trees and spines have been found in many neurodegenerative diseases, including Alzheimer's disease (AD), in which the deficits of melatonin signal pathway were reported. Melatonin receptor 2 (MT2) is widely expressed in the hippocampus and mediates the biological functions of melatonin. It is known that melatonin application is protective to dendritic abnormalities in AD. However, whether MT2 is involved in the neuroprotection and the underlying mechanisms are not clear. Here, we first found that MT2 is dramatically reduced in the dendritic compartment upon the insult of oligomer Aβ. MT2 activation prevented the Aβ‐induced disruption of dendritic complexity and spine. Importantly, activation of MT2 decreased cAMP, which in turn inactivated transcriptional factor CCAAT/enhancer‐binding protein α(C/EBPα) to suppress miR‐125b expression and elevate the expression of its target, GluN2A. In addition, miR‐125b mimics fully blocked the protective effects of MT2 activation on dendritic trees and spines. Finally, injection of a lentivirus containing a miR‐125b sponge into the hippocampus of APP/PS1 mice effectively rescued the dendritic abnormalities and learning/memory impairments. Our data demonstrated that the cAMP‐C/EBPα/miR‐125b/GluN2A signaling pathway is important to the neuroprotective effects of MT2 activation in Aβ‐induced dendritic injuries and learning/memory disorders, providing a novel therapeutic target for the treatment of AD synaptopathy.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer’s disease via C/EBPα/miR‐125b pathway

Tang

Wang

et al. 2019

Aging Cell

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“…As novel biomarkers and regulatory small molecules, miRNAs play important roles in diagnosing and treating several diseases (Chen et al, ; Wang et al, ). The mechanism lies in binding the 3′ untranslated region (3′UTR) of the target gene.…”

Section: Introductionmentioning

confidence: 99%

MiR‐21‐5p/dual‐specificity phosphatase 8 signalling mediates the anti‐inflammatory effect of haem oxygenase‐1 in aged intracerebral haemorrhage rats

Ouyang

Wang

et al. 2019

Aging Cell

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Intracerebral haemorrhage (ICH) is a severe neurological disorder caused by bleeding within the brain tissue. Inflammation has been implicated in ICH pathogenesis and is a potential therapeutic target for ICH. Haemin, an activator of haem oxygenase-1 (HO-1), rapidly increases HO-1 protein expression and activity and has been shown to distinctly affect anti-inflammatory functions after central nervous system (CNS) injury. However, less is known about the mechanisms that underlie the antiinflammatory effects of haemin in aged rats post-ICH. Here, we performed microarray analysis to identify miRNAs that respond strongly to HO-1 regulation in ICH rats and found that miR-21-5p induced the most significant change. Using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and Gene Ontology (GO) analysis, we focused on dual-specificity phosphatase 8 (DUSP8) from the predicted miR-21-5p targets. Luciferase reporter assays confirmed that miR-21-5p bound directly to DUSP8. MiR-21-5p upregulation in vitro downregulated DUSP8 expression. Importantly, intracerebroventricularly injecting antagomir for miR-21-5p (A-miR-21-5p), which was used to inhibit miR-21-5p in aged ICH rats, significantly reduced the neurological defects, repaired cognitive impairment, alleviated blood-brain barrier (BBB) permeability, inhibited neuronal apoptosis posthaemorrhage and accelerated haematoma absorption. In addition, serum miR-21-5p levels were notably elevated in patients relative to healthy individuals and were correlated with National Institutes of Health Stroke Scale (NIHSS) scores and clinical outcomes. In summary, A-miR-21-5p increased HO-1 expression in cerebral haematomas, thus eliciting the

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A near‐infrared probe for detecting and interposing amyloid beta oligomerization in early Alzheimer's disease

Moreno-González

Xie

et al. 2022

Alzheimer's & Dementia

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Background The misfolding and deposition of amyloid beta (Aβ) in human brain is the main hallmark of Alzheimer's disease (AD) pathology. One of the drivers of Alzheimer´s pathogenesis is the production of soluble oligomeric Aβ, which could potentially serve as a biomarker of AD. Methods Given that the diphenylalanine (FF) at the C‐terminus of Aβ fragments plays a key role in inducing the AD pathology, based on the hydrophobic structure of FF, we synthesized a near‐infrared BF2‐dipyrrolmethane fluorescent imaging probe (NB) to detect both soluble and insoluble Aβ. Results We found that NB not only binds Aβ, particularly oligomeric Aβ, but also interposes self‐assembly of Aβ through π‐π interaction between NB and FF. Conclusion This work holds great promise in the early detection of AD and may also provide an innovative approach to decelerate and even halt AD onset and progression.

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A Novel MicroRNA-124/PTPN1 Signal Pathway Mediates Synaptic and Memory Deficits in Alzheimer’s Disease

Cited by 180 publications

References 46 publications

Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer’s disease via C/EBPα/miR‐125b pathway

Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer’s disease via C/EBPα/miR‐125b pathway

MiR‐21‐5p/dual‐specificity phosphatase 8 signalling mediates the anti‐inflammatory effect of haem oxygenase‐1 in aged intracerebral haemorrhage rats

A near‐infrared probe for detecting and interposing amyloid beta oligomerization in early Alzheimer's disease

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