Wnt Signaling Rescues Amyloid Beta-Induced Gut Stem Cell Loss
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE181844 | GEO | 2021/12/31
REPOSITORIES: GEO
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Project description:To investigate miRNAs that implicate the process of adipogenesis by interacting with canonical Wnt/β-catenin signaling pathway, we constructed two cell models at first, and then investigated the expression profile of microRNAs by using Microarray. Based on the data of high throughput microarray, we identified 18 miRNAs which might promote adipogenesis by repressing WNT signaling, including mir-210, mir-148a, mir-194, mir-322 etc. On the other hand, we also identified 29 miRNAs which might repress adipogenesis by activation of WNT signaling, including mir-344, mir-27, and mir-181. The target genes involved in WNT signaling pathway of these identified miRNAs were also predicted through online tools. Two cell models of 3T3-L1, i.e. activation and suppression of WNT signaling including four samples, i.e. preadipocytes, mature adipocytes (MDI induction), Lithium treated preadipocytes, MDI induction of Lithium treated preadipocytes. Each sample was replicated in triplicate.
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Project description:Our previous work in a Drosophila model of Alzheimer's disease (AD) has shown that we can intervene into the pathways to slow or prevent AD progression. Lithium was able to rescue toxicity in the Drosophila AD model which corresponded with a reduction in Abeta levels. Furthermore, we have demonstrated that Lithium affects Abeta protein translation. To this end, we were interested in studying the effect of Lithium on Abeta using microarray analyses, to determine if we could uncover any interesting downstream pathways. Flies were expressing a mutant version of Abeta, the Arctic mutation, which increases the aggregation or production of Abeta (UAS-ArcAb42/+;elavGS/+). We collected flies 2 days post eclosion that either had no Arctic Abeta protein, or expressed Arctic with or without Lithium treatment for 17 days post eclosion. Samples were homogenised using RLT buffer with betamercaptoethanol.
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Project description:INTRODUCTION: The pathogenicity at differing points along the aggregation pathway of many fibril-forming proteins associated with neurodegenerative diseases is unclear. Understanding the effect of different aggregation states of these proteins on cellular processes is essential to enhance understanding of diseases and provide future options for diagnosis and therapeutic intervention.</br>OBJECTIVES:To establish a robust method to probe the metabolic changes of neuronal cells and use it to monitor cellular response to challenge with three amyloidogenic proteins associated with neurodegenerative diseases in different aggregation states.</br>METHOD: Neuroblastoma SH-SY5Y cells were employed to design a robust routine system to perform a statistically rigorous NMR metabolomics study into cellular effects of sub-toxic levels of alpha-synuclein, amyloid-beta 40 and amyloid-beta 42 in monomeric, oligomeric and fibrillar conformations.</br>RESULTS: This investigation developed a rigorous model to monitor intracellular metabolic profiles of neuronal cells through combination of existing methods. This model revealed eight key metabolites that are altered when neuroblastoma cells are challenged with proteins in different aggregation states. Metabolic pathways associated with lipid metabolism, neurotransmission and adaptation to oxidative stress and inflammation are the predominant contributors to the cellular variance and intracellular metabolite levels. The observed metabolite changes for monomer and oligomer challenge may represent cellular effort to counteract the pathogenicity of the challenge, whereas fibrillar challenge is indicative of system shutdown. This implies that although markers of stress are more prevalent under oligomeric challenge the fibrillar response suggests a more toxic environment.</br>CONCLUSION: This approach is applicable to any cell type that can be cultured in a laboratory (primary or cell line) as a method of investigating how protein challenge affects signalling pathways, providing additional understanding as to the role of protein aggregation in neurodegenerative disease initiation and progression.
2018-06-11 | MTBLS455 | MetaboLights
Project description:Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. Comprehensive transcriptome analysis was employed to validate the capacity of three prioritized compounds to remodel the ER proteostasis environment, and to assess the prefential activation of ATF6 transcriptional targets relative to targets of the IRE1/XBP1s and PERK arms of the UPR.
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Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.
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