WGS/RNA-seq pair of an inflammatory hepatocellular adenoma (IHCA)
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PROVIDER: EGAS00001003025 | EGA |
REPOSITORIES: EGA
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Project description:Microglia and monocyte-derived macrophages (MDM) are key players in coping with Alzheimer's disease (AD). In amyloidosis mouse models, activation of microglia was found to be TREM2-dependent. Here, using Trem2-/-5xFAD mice, we assessed whether MDM act via a TREM2-dependent pathway. We adopted a treatment protocol targeting the programmed cell death ligand-1 (PD-L1) immune checkpoint, previously shown to modify AD via MDM involvement. Blocking PD-L1 in Trem2-/-5xFAD mice resulted in cognitive improvement and reduced levels of water-soluble amyloid beta (Aβ)1-42 with no effect on amyloid plaque burden. Single-cell RNA sequencing revealed that MDM, derived from both Trem2-/- and Trem2+/+5xFAD mouse brains, express a unique set of genes encoding scavenger receptors (e.g. Mrc1, Msr1). Blocking monocytes trafficking using anti-CCR2 antibody completely abrogated the cognitive improvement induced by anti-PD-L1 in Trem2-/-5xFAD mice, and similarly but to lower extent in Trem2+/+5xFAD mice. These results highlight a TREM2-independent disease-modifying activity of MDM in amyloidosis mouse model.
2021-10-24 | GSE176085 | GEO
Project description:Exercise interventions are beneficial for reducing the risk of age-related diseases, including amyloidosis, but the underlying molecular links remain unelucidated. Here, we investigated the protective role of interval exercise training in a mouse model of age-related systemic apolipoprotein A-II amyloidosis (AApoAII) and elucidated potential mechanisms. Mice subjected to sixteen weeks of exercise improved whole-body physiologic functions and exhibited substantial inhibition of amyloidosis, particularly in the liver and spleen. Exercise activated the hepatic p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and the downstream transcription factor tumor suppressor p53. This activation resulted in elevated expression and phosphorylation of heat shock protein beta-1 (HSPB1), a chaperone that defends against protein aggregation. In the amyloidosis-induced mice, the hepatic p38 MAPK-related adaptive responses were additively enhanced by exercise. We observed that with exercise, greatly increased amounts of phosphorylated HSPB1 accumulated at amyloid deposition areas, which we suspect to inhibit amyloid fibril formation. Collectively, our findings conclude exercise-activated, specific chaperone prevention of amyloidosis, and suggest that exercise may amplify intracellular stress-related protective adaptation pathways against age-associated disorders such as amyloidosis.
2022-03-04 | GSE192521 | GEO
Project description:The amyloidoses constitute a group of diseases occurring in humans and animals that are characterized by abnormal deposits of aggregated proteins in organs, affecting their structure and function. In the Abyssinian cat breed, a familial form of renal amyloidosis has been described. In this study, multi-omics analyses were applied and integrated to explore some aspects of the unknown pathogenetic processes in cats. Whole-genome sequences of two affected Abyssinians and 195 controls of other breeds (part of the 99 Lives initiative) were screened to prioritize potential disease-associated variants. Proteome and miRNAome from formalin-fixed paraffin-embedded kidney specimens of fully necropsied Abyssinian cats, three affected and three non-amyloidosis affected were characterized. While the trigger of the disorder remains unclear, overall, i) 35,960 genomic variants were detected; ii) 215 and 56 proteins were identified as exclusive or overexpressed in the affected and control kidneys, respectively; iii) 60 miRNAs were differentially expressed, 20 of which are newly described. With omics data integration, the general conclusions are:i) the familial amyloid renal form in Abyssinians is not a simple monogenic trait ii) amyloid deposition is not triggered by mutated amyloidogenic proteins but is a mix of proteins codified by wild-type genes iii) the form is biochemically classifiable as AA amyloidosis.
2021-09-10 | PXD024140 | Pride
Project description:Amyloid light chain amyloidosis (AL) is an incurable protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains accumulate as amyloid fibrils in vital organs and cause multi-organ dysfunction that can be rapidly fatal. Current treatment regimens, which include proteasome inhibitors, were developed for the treatment of the more common plasma cell disease multiple myeloma and have demonstrated efficacy in AL amyloidosis. However, use of these agents is frequently limited due to multi-organ dysfunction at presentation, resulting in a median survival of 2-3 years and underscoring the need for novel therapies. By analyzing bone marrow-derived plasma cells from 44 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins that can potentially be targeted by recently-developed BH3 mimetics. In particular, we find that clonal plasma cells are highly dependent on the pro-survival MCL-1 and undergo apoptosis in response to single-agent treatment with an MCL-1 inhibitor. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, which is currently the standard of care for this disease, via the stabilization of Noxa and its direct inhibitory binding to MCL-1. BCL-2 inhibition with the FDA-approved inhibitor venetoclax (ABT-199) sensitizes plasma cells to bortezomib treatment and other front-line therapies, which can be observed in vitro and in vivo. Mass spectrometry-based proteomic analysis reveals changes in signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapy. Overall, our results indicate that BH3 mimetics may be highly effective therapies for AL amyloidosis that exploit inherent and induced dependencies on pro-survival proteins.
2022-10-03 | PXD024119 | Pride
Project description:Amyloidosis is a disorder characterized by the formation of extracellular amyloid deposits. Immunoglobulin light-chain amyloidosis the most common form of amyloidosis can appear as a local disorder presented with mild symptoms or as a life threatening systemic disease. Identification of the proteins forming amyloid fibrils is essential for the diagnosis of the disease and knowledge about the overall protein composition of the deposits may lead to a larger understanding of the deposition events thereby facilitating a more detailed picture of the molecular pathology. In this study, we investigated the protein composition of AL amyloid deposits isolated from human eyelid, conjunctival and orbital specimens. Deposits and internal control tissue (patient tissue without apparent deposits) were procured by laser capture microdissection. Proteins in the captured amyloid and control samples were identified by liquid chromatography tandem mass spectrometry and subsequently quantified using the label-free mass spectrometry quantification method exponential modified Protein Abundance Index. Immunoglobulin light chain kappa or lambda was revealed to be the most predominant protein in the amyloid deposits. In addition, the protein profiles identified apolipoprotein E and serum amyloid P component to be associated with the immunoglobulin light chain deposits across all three tissues analyzed. The method used in this study provides high sensitivity and specificity of typing amyloidosis and may provide additional information on the pathology of amyloidosis.
2014-05-29 | PXD000743 | Pride
Project description:Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer’s disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 (Arg1) is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported Arg1 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, it remains unclear how Arg1 deficiency in these cells impacts the whole brain to promote amyloidosis. Herein, we aim to determine how Arg1 deficiency driven by LysM restriction during amyloidosis affects fundamental neurodegenerative pathways at the transcriptome level. By applying several bioinformatic tools and analyses, we found that amyloid-β (Aβ) stimulated transcriptomic signatures in autophagy-related pathways and myeloid cells' inflammatory response. At the same time, myeloid Arg1 deficiency during amyloidosis promoted gene signatures of lipid metabolism, myelination, and migration of myeloid cells. Focusing on Aβ associated glial transcriptomic signatures, we found myeloid Arg1 deficiency up-regulated glial gene transcripts that positively correlated with Aβ plaque burden. We also observed that Aβ preferentially activated disease-associated microglial signatures to increase phagocytic response, whereas myeloid Arg1 deficiency selectively promoted homeostatic microglial signature that is non-phagocytic. These transcriptomic findings suggest a critical role for proper Arg1 function during normal and pathological challenges associated with amyloidosis. Furthermore, understanding pathways that govern Arg1 metabolism may provide new therapeutic opportunities to rebalance immune function and improve microglia/macrophage fitness.
2021-04-15 | GSE172108 | GEO
Project description:Here we studied cellular level changes of hippocampal cells by unbiased single cell RNA-seq using AD mouse models bearing amyloid pathology (PS2APP), or amyloid and tau combined pathology (TauPS2APP) by single cell RNA-seq. We identified 16 different cell types and further characterized responses of microglia, oligodendrocytes, astrocytes and T cells to amyloidosis only and amyloid plus tau combined pathology. Both mouse models exhibited robust microglial responses. We also found distinct responses of oligodendrocytes to different AD pathologies. We observed increased T cell numbers in both mouse models. Current dataset presents diverse transcriptomic responses to AD pathology and provides resources to study molecular mechanisms underlying disease onset and progression.
2021-11-12 | GSE181786 | GEO
Project description:Amyloidosis is a group of diseases caused by extracellular accumulation of fibrillar polypeptide aggregates. So far, diagnosis is performed by Congo red staining of tissue sections in combination with polarization microscopy. Subsequent identification of the causative protein by immunohistochemistry harbors some difficulties regarding sensitivity and specificity. Mass spectrometry-based approaches have been demonstrated to constitute a reliable method to supplement typing of amyloidosis, but still depend on Congo red staining. In the present study matrix-assisted laser desorption/ionization mass spectrometry imaging coupled with ion mobility separation (MALDI-IMS MSI) was used to investigate amyloid deposits in formalin-fixed and paraffin-embedded tissue samples. We designed a peptide filter method enabling the identification of tryptic peptides derived from amyloidogenic and amyloid-associated proteins without additional tandem mass spectrometry. Utilizing the filter we found a universal peptide signature for amyloidoses independent from amyloid type and histoanatomical localization. Examining a validation cohort of cardiac biopsies including 66 amyloid and 31 non-amyloid cases, amyloidosis was diagnosed with high sensitivity and specificity. Furthermore, differences in the peptide composition of AL-lambda and ATTR amyloid were revealed and used to build a reliable classification model. Integrating the peptide filter in MALDI-IMS MSI analysis we developed a bioinformatics workflow facilitating the identification and classification of amyloidosis in a less time and sample consuming experimental setup. Our findings demonstrate also the feasibility to investigate the amyloid's composition, thus paving the way to establish classification models for the diverse types of amyloidoses and to shed further light on the complex process of amyloidogenesis.
2017-10-16 | PXD005960 | Pride
Project description:Immunoglobulin light chain (LC) amyloidosis is a life-threatening disease whose understanding and treatment is complicated by vast numbers of patient-specific mutations. To address molecular origins of the disease, we explored 14 patient-derived and engineered proteins related to κ1-family germline genes IGKVLD-33*01 and IGKVLD-39*01. Hydrogen-deuterium exchange mass spectrometry analysis of local conformational dynamics in full-length recombinant LCs and their fragments was integrated with studies of thermal stability, proteolytic susceptibility, amyloid formation, and amyloidogenic sequence propensities using spectroscopic, electron microscopic and bioinformatics tools. The results were mapped on the atomic structures of native and fibrillary proteins. Proteins from two κ1 subfamilies showed unexpected differences. Compared to their germline counterparts, amyloid LC related to IGKVLD-33*01 was less stable and formed amyloid faster, whereas amyloid LC related to IGKVLD-39*01 had similar stability and formed amyloid slower. These and other differences suggest different major factors influencing amyloid formation. In 33*01-related amyloid LC, these factors involved mutation-induced destabilization of the native structure and probable stabilization of amyloid. The atypical behavior of 39*01-related amyloid LC tracked back to increased dynamics/exposure of amyloidogenic segments in βC’V and βEV that could initiate aggregation, combined with decreased dynamics/exposure near the C23-Cys88 disulfide whose rearrangement is rate-limiting to amyloidogenesis. The results suggest distinct amyloidogenic pathways for closely related LCs and point to the antigen-binding regions CDR1 and CDR3, which are linked via the conserved internal disulfide, as key factors in amyloid formation by various LCs.
2023-05-23 | PXD039682 | Pride
Project description:We found some novel miRNA that targets SIRT1 may contribute to the pathogenesis in AD mouse model. We first identified that SIRT1 is significantly reduced in Alzheimer patient`s precentral gyrus and 5XFAD mice. To determine whether the strategy of inhibiting some miRNA affects AD pathology, we synthesized antisense oligonucleotides of miRNA (miRNA ASO) and studied this sequence in the brain of 5XFAD through direct intracerebral ventricular injection using stereotaxic instrument. We identified miRNA ASO significantly reduced amyloid beta plaque and amyloid production enzyme. Importantly, the attenuation of amyloid beta plaques through miRNA ASO was caused by a phagocytic activity of glial cells, by which it can directly target CD36. miRNA ASO also decreases inflammatory responses. These results inhibit neuronal loss caused by amyloid beta and leading to improvement of cognitive impairment. These insights of miRNA ASO suggests as therapeutic scope against AD pathology.
2019-12-27 | GSE142633 | GEO