NEAT1 regulates neuroglial cell mediating Aβ clearance via the epigenetic regulation of endocytosis-related genes expression

Wang, Ziqiang; Zhao, Yuan; Xu, Ning; Zhang, Shikuan; Wang, Songmao; Mao, Yunhao; Zhu, Yuanchang; Li, Bing; Jiang, Yuyang; Tan, Ying; Xie, Weidong; Yang, Burton B.; Zhang, Yaou

doi:10.1007/s00018-019-03074-9

Cited by 93 publications

(113 citation statements)

References 61 publications

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“…The rescuing effects of metformin further confirmed by in-vivo studies. In our previous study, we detected the mRNA levels of Neat1 in 3-month-old APP/PS1 double transgenic mouse, and found reduced Neat1 expression compared with C57 mice [16]. In present study, these nearly 3 months old AD mice were observed an increased in the level of Neat1 and Fzd3 mRNA in the hippocampus of metformin treated group compared to control group treated with ddH2O (Fig 6B and C).…”

Section: Resultssupporting

confidence: 65%

“…The down-regulation of NEAT1 expression contributed to amyloid-β deposition, via inhibiting expression of multi endocytosis related genes. Through interaction with P300/CBP complex, NEAT1 regulated expression of these genes via affecting H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) in the promotor region of these genes[16]. In this investigation, we found that NEAT1 involves AD progression also through dysregulation of glycolysis and up-regulation of p-tau.…”

Section: Discussionmentioning

confidence: 82%

“…In our previous study of RNA immunoprecipitation (RIP) assay we have shown that p300/CBP pulled down several fragments of NEAT1. Moreover NEAT1 also co-localized with p300/CBP therefore influence its acyltransferase activity by direct interaction[16]. To reveal the potential mechanism how NEAT1 regulates FZD3 transcription, we designed four paired primers (P1, P2, P3, P4) across the promoter region (−1000bp to +1000bp) of FZD3 and then subjected to ChIP-PCR assay to identify its regulatory mechanism.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to its involvement in the regulation of multiple genes expression by modulating their transcriptional activities NEAT1 also implicated in some neuronal loss diseases and neurodegenerative processes, such as amyotrophic lateral sclerosis, traumatic brain injury and Huntington’s disease., However very little is known about the precise roles of NEAT1 in AD progression [13–15]. In our recent study, we found that NEAT1 expression down-regulated in the early stage of AD and its downregulation contribute to amyloid-β deposition [16] and the change of glucose metabolism.…”

Section: Introductionmentioning

confidence: 99%

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NEAT1 involves Alzheimer’s Disease (AD) progression via regulation of glycolysis and P-tau

Zhao

Wang

Mao

et al. 2019

Preprint

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22Nuclear paraspeckles assembly transcript 1 (NEAT1) is a well-known long noncoding 23 RNA (LncRNA) with unclear mechanism in Alzheimer's disease (AD) progression. 24 Here, we found that NEAT1 down-regulates in the early stage of AD patients and 25 APPswe/PS1dE9 mouse. Moreover, knockdown of NEAT1 induced 26 de-polymerization of microtubule (MT) and axonal retraction of nerve cells by 27 dysregulation of the FZD3/GSK3β/p-tau signaling pathway. Histone acetylation 28 analysis at the Frizzled Class Receptor 3 (FZD3) promoter shows a marked decreased 29in the levels of the H3K27 acetylation (H3K27Ac) after NEAT1 knockdown. Our 30 data demonstrates that P300/CBP recruited by NEAT1 to the FZD3 promoter and 31 induced its transcription via histone acetylation. In recent years a growing number of 32 evidences have shown an abnormal brain glucose homeostasis in AD. In the present 33 study we also observed an abnormal brain glucose homeostasis and enhanced sirtuin1 34 (SIRT1) activity after knockdown of NEAT similarly as in AD. Our results provided 35 insight into the role of NEAT1 in the maintenance of MT stability and its effect on 36 glucose metabolism during early stages of AD. 37 38 39 40 42population that involves complex neurodegenerative alterations. There are several 43 hypotheses to explain the basis of AD. Among them, the cholinergic, amyloid-β (Aβ) 44 and tau hypotheses are the most recognized doctrine [1][2][3][4]. Currently, the available 45 therapy of enhancing the acetylcholine response is not much satisfactory, and the 46 trials targeting Aβ in AD repeatedly failed [5]; therefore, the microtubule associated 47 protein tau (MAPT) hypothesis has gained much attention. In animal model, 48 hyper-phosphorylated tau induces neurofibrillary tangles and microtubule 49 disintegration, triggering the death of neurons [6, 7]; but, the precise molecular 50 mechanism leading to the hyper-phosphorylation of tau remains unclear. 52Nuclear enriched abundant transcript 1(NEAT1) is a type of nuclear bodies exist in 53 highly organized manner in mammalian nuclei to control gene expression and 54 epigenetic events, is critical for the formation and maintenance of paraspeckles, [8, 9]. 55The NEAT1 gene has two isoforms, NEAT1v1 (3.7 kb in length) and NEAT1v2 (23 56 kb in length). NEAT1v2 binds directly to the paraspeckles proteins P54nrb/NONO 57 and SFPQ/PSF, which results in the recruitment of NEAT1v1 and PSPC1 [10]. The 58 primary function of paraspeckles is to sequester A-to-I hyper-edited RNAs which 59 composed of an inverted repeat of Alu elements (IRAlus) in the nucleus to prevent the 60 incorrect translation of edited RNAs. Chen and Carmichael investigated that, NEAT1 61 knockdown leads to the collapse of paraspeckles as well as increased export of mRNA 62containing IRAlus, suggesting a close relationship between NEAT1 and the function 63 of nuclear retention [12]. In addition to its involvement in the regulation of multiple 64 genes expression by modulating their transcriptional activities NEAT1 also 65 impli...

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Section: Resultssupporting

confidence: 65%

Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NEAT1 involves Alzheimer’s Disease (AD) progression via regulation of glycolysis and P-tau

Zhao

Wang

Mao

et al. 2019

Preprint

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“…It has previously been shown that multiple PTM amyloid‐β peptides were observed in the brain of AD patients 29 . For example, in a previous study, it was demonstrated that acetylation and crotonylation of histones potentially influenced Aβ1‐42, thereby regulating the pathology of dementia 30 . Moreover, several strategies have been developed to inhibit Aβ aggregation or to promote Aβ clearance for the prevention and treatment of BCCAO‐induced cognitive impairment 31‐33 .…”

Section: Discussionmentioning

confidence: 99%

Donepezil down‐regulates propionylation, 2‐hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation in the brain of bilateral common carotid artery occlusion‐induced vascular dementia rats

Wang

Lü

Gao

et al. 2020

Clin Exp Pharma Physio

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Vascular dementia (VaD), caused by stroke or small vessel disease, is the second‐most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris water maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Aβ1‐42 in BCCAO rats by enzyme‐linked immunosorbent assay. Post‐translational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlights the importance of PTMs in neurodegenerative diseases. In this study, we used western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2‐hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl‐PTMs.

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Development of Lysine Crotonyl‐Mimic Probe to Covalently Identify H3K27Cr Interacting Proteins

Guo,

Wang,

et al. 2023

Chemistry A European J

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Histone lysine crotonylation (Kcr) is one newly discovered acylation modification and regulates numerous pathophysiological processes. The binding affinity between Kcr and its interacting proteins is generally weak, which makes it difficult to effectively identify Kcr‐interacting partners. Changing the amide of crotonyl to an ester increased reactivity with proximal cysteines and retained specificity for Kcr antibody. We then designed the probe “H3g27Cr” by incorporating the ester functionality into a H3K27 peptide. Using this probe, we successfully identified multiple Kcr‐interacting partners including STAT3, which had not reported previously. Further experiments suggested that STAT3 possibly could form complexes with Histone deacetylase HDACs to downregulate the acetylation and crotonylation of Histone H3K27. Our unique design provided intriguing tools to further explore Kcr‐interacting proteins and elucidate their working mechanisms.

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NEAT1 regulates neuroglial cell mediating Aβ clearance via the epigenetic regulation of endocytosis-related genes expression

Cited by 93 publications

References 61 publications

NEAT1 involves Alzheimer’s Disease (AD) progression via regulation of glycolysis and P-tau

NEAT1 involves Alzheimer’s Disease (AD) progression via regulation of glycolysis and P-tau

Donepezil down‐regulates propionylation, 2‐hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation in the brain of bilateral common carotid artery occlusion‐induced vascular dementia rats

Development of Lysine Crotonyl‐Mimic Probe to Covalently Identify H3K27Cr Interacting Proteins

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