Dataset Information

Long Noncoding RNA NEAT1 Aggravates A?-Induced Neuronal Damage by Targeting miR-107 in Alzheimer's Disease.

ABSTRACT: PURPOSE:Alzheimer's disease (AD) is the most common neurodegenerative disease, with a rising prevalence worldwide. Long noncoding RNAs (lncRNAs) have been found to play important roles in the development and treatment of AD. However, the exact role of lncRNA nuclear enriched abundant transcript 1 (NEAT1) in neuronal damage in AD is largely unknown. MATERIALS AND METHODS:The AD model was established in SH-SY5Y and SK-N-SH cells via treatment with amyloid ?1-42 (A?). The expression of NEAT1 and microRNA-107 (miR-107) was measured by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were detected by MTT assay, immunocytochemistry, and flow cytometry. The expression of phosphorylated tau protein (p-Tau) was measured by Western blot. The interaction between NEAT1 and miR-107 was explored by bioinformatics analysis, luciferase activity, and RNA immunoprecipitation assays. RESULTS:NEAT1 expression was enhanced in A?-treated SH-SY5Y and SK-N-SH cells, and its knockdown attenuated A?-induced inhibition of viability and promotion of apoptosis and p-Tau levels. NEAT1 was indicated as a decoy of miR-107. miR-107 abundance was reduced in A?-treated cells, and its overexpression reversed A?-induced injury. Moreover, interference of miR-107 abated silencing of NEAT1-mediated inhibition of neuronal damage in A?-treated SH-SY5Y and SK-N-SH cells. CONCLUSION:LncRNA NEAT1 aggravated A?-induced neuronal damage by sponging miR-107, indicating a novel avenue for treatment of AD.

SUBMITTER: Ke S

PROVIDER: S-EPMC6597469 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Long Noncoding RNA NEAT1 Aggravates Aβ-Induced Neuronal Damage by Targeting miR-107 in Alzheimer's Disease.

Ke Sha S Yang Zhaohui Z Yang Fei F Wang Xiaoming X Tan Juan J Liao Bo B

Yonsei medical journal 20190701 7

<h4>Purpose</h4>Alzheimer's disease (AD) is the most common neurodegenerative disease, with a rising prevalence worldwide. Long noncoding RNAs (lncRNAs) have been found to play important roles in the development and treatment of AD. However, the exact role of lncRNA nuclear enriched abundant transcript 1 (NEAT1) in neuronal damage in AD is largely unknown.<h4>Materials and methods</h4>The AD model was established in SH-SY5Y and SK-N-SH cells via treatment with amyloid β<sub>1-42</sub> (Aβ). The ...[more]

PMID: 31250578

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Project description:BackgroundDespite its identification as a key checkpoint regulator of microglial activation in Alzheimer's disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood.MethodologyAccumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1-/- mice using immunohistochemistry, western blotting, transcriptomic and quantitative real time PCR analyses of purified microglia. Flow cytometry based, in-vivo Aβ uptake assays are used for characterization of the effects of CX3CR1-signaling on microglial phagocytosis and lysosomal acidification as indicators of clearance of methoxy-X-04+ fibrillar Aβ. Lastly, we use Y-maze testing to analyze the effects of Cx3cr1 deficiency on working memory.ResultsDisease progression in 5xFAD;Cx3cr1-/- mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement. Microglial Aβ phagocytosis and lysosomal acidification in 5xFAD;Cx3cr1-/- mice is impaired in-vivo. Interestingly, Cx3cr1 deficiency results in heighted accumulation of neurotoxic, oligomeric Aβ, along with severe neuritic dystrophy, preferential loss of post-synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA, coupled with qRT-PCR using purified microglia from 6 month-old mice indicate dysregulated TGFβ-signaling and heightened ROS metabolism in 5xFAD;Cx3cr1-/- mice. Lastly, microglia in 6 month-old 5xFAD;Cx3cr1-/- mice express a 'degenerative' phenotype characterized by increased levels of Ccl2, Ccl5, Il-1β, Pten and Cybb along with reduced Tnf, Il-6 and Tgfβ1 mRNA.ConclusionsCx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering increased accumulation of neurotoxic Aβ species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFβ-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1-/- mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory.

Dataset Information

Long Noncoding RNA NEAT1 Aggravates A?-Induced Neuronal Damage by Targeting miR-107 in Alzheimer's Disease.

Publications

Long Noncoding RNA NEAT1 Aggravates Aβ-Induced Neuronal Damage by Targeting miR-107 in Alzheimer's Disease.

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