-
1دورية أكاديمية
المؤلفون: Muhammad Ali, Pierre Garcia, Laetitia P. Lunkes, Alessia Sciortino, Melanie Thomas, Tony Heurtaux, Kamil Grzyb, Rashi Halder, Djalil Coowar, Alex Skupin, Luc Buée, David Blum, Manuel Buttini, Enrico Glaab
المصدر: Cell Death Discovery, Vol 10, Iss 1, Pp 1-19 (2024)
مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
الوصف: Abstract Alzheimer’s disease (AD) progression and pathology show pronounced sex differences, but the factors driving these remain poorly understood. To gain insights into early AD-associated molecular changes and their sex dependency for tau pathology in the cortex, we performed single-cell RNA-seq in the THY-Tau22 AD mouse model. By examining cell type-specific and cell type-agnostic AD-related gene activity changes and their sex-dimorphism for individual genes, pathways and cellular sub-networks, we identified both statistically significant alterations and interpreted the upstream mechanisms controlling them. Our results confirm several significant sex-dependent alterations in gene activity in the THY-Tau22 model mice compared to controls, with more pronounced alterations in females. Both changes shared across multiple cell types and cell type-specific changes were observed. The differential genes showed significant over-representation of known AD-relevant processes, such as pathways associated with neuronal differentiation, programmed cell death and inflammatory responses. Regulatory network analysis of these genes revealed upstream regulators that modulate many of the downstream targets with sex-dependent changes. Most key regulators have been previously implicated in AD, such as Egr1, Klf4, Chchd2, complement system genes, and myelin-associated glycoproteins. Comparing with similar data from the Tg2576 AD mouse model and human AD patients, we identified multiple genes with consistent, cell type-specific and sex-dependent alterations across all three datasets. These shared changes were particularly evident in the expression of myelin-associated genes such as Mbp and Plp1 in oligodendrocytes. In summary, we observed significant cell type-specific transcriptomic changes in the THY-Tau22 mouse model, with a strong over-representation of known AD-associated genes and processes. These include both sex-neutral and sex-specific patterns, characterized by consistent shifts in upstream master regulators and downstream target genes. Collectively, these findings provide insights into mechanisms influencing sex-specific susceptibility to AD and reveal key regulatory proteins that could be targeted for developing treatments addressing sex-dependent AD pathology.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2058-7716Test
-
2دورية أكاديمية
المؤلفون: Yolanda Pires‐Afonso, Arnaud Muller, Kamil Grzyb, Anaïs Oudin, Yahaya A. Yabo, Carole Sousa, Andrea Scafidi, Aurélie Poli, Antonio Cosma, Rashi Halder, Djalil Coowar, Anna Golebiewska, Alexander Skupin, Simone P. Niclou, Alessandro Michelucci
المصدر: Molecular Oncology, Vol 16, Iss 17, Pp 3167-3191 (2022)
مصطلحات موضوعية: ACOD1/IRG1, glioblastoma, heterogeneity, metabolic reprogramming, single‐cell RNA‐sequencing, tumour‐associated microglia/macrophages, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: In glioblastoma (GBM), tumour‐associated microglia/macrophages (TAMs) represent the major cell type of the stromal compartment and contribute to tumour immune escape mechanisms. Thus, targeting TAMs is emerging as a promising strategy for immunotherapy. However, TAM heterogeneity and metabolic adaptation along GBM progression represent critical features for the design of effective TAM‐targeted therapies. Here, we comprehensively study the cellular and molecular changes of TAMs in the GL261 GBM mouse model, combining single‐cell RNA‐sequencing with flow cytometry and immunohistological analyses along GBM progression and in the absence of Acod1 (also known as Irg1), a key gene involved in the metabolic reprogramming of macrophages towards an anti‐inflammatory phenotype. Similarly to patients, we identify distinct TAM profiles, mainly based on their ontogeny, that reiterate the idea that microglia‐ and macrophage‐like cells show key transcriptional differences and dynamically adapt along GBM stages. Notably, we uncover decreased antigen‐presenting cell features and immune reactivity in TAMs along tumour progression that are instead enhanced in Acod1‐deficient mice. Overall, our results provide insight into TAM heterogeneity and highlight a novel role for Acod1 in TAM adaptation during GBM progression.
وصف الملف: electronic resource
النص الكامل