Alzheimer's disease‐induced phagocytic microglia express a specific profile of coding and non‐coding RNAs

Scoyni, Flavia; Giudice, Luca; Väänänen, Mari‐Anna; Downes, Nicholas; Korhonen, Paula; Choo, Xin Yi; Välimäki, Nelli‐Noora; Mäkinen, Petri; Korvenlaita, Nea; Rozemuller, Annemieke J; de Vries, Helga E; Polo, Jose; Turunen, Tiia A; Ylä‐Herttuala, Seppo; Hansen, Thomas B; Grubman, Alexandra; Kaikkonen, Minna U; Malm, Tarja

doi:10.1002/alz.13502

Cited by 3 publications

(2 citation statements)

References 72 publications

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“…Notable AD-associated TFs identified by TRIPS in both AD datasets include GATA3, CEBPA, FOS, SPI1, STAT1, and NFKB1. GATA3, which is known to promote inflammation, is activated in phagocytic microglia [58,64,65]. FOS is involved in microglial development and in promoting the inflammatory "disease-associated microglia" cell state [66,67].…”

Section: Application To Alzheimer's Diseasementioning

confidence: 99%

Identification of transcriptional regulators using a combined disease module identification and prize-collecting Steiner tree approach

Galindez,

Lopez,

Blumenthal

et al. 2024

Preprint

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Transcription factors play important roles in maintaining normal biological function, and their dys-regulation can lead to the development of diseases. Identifying candidate transcription factors involved in disease pathogenesis is thus an important task for deriving mechanistic insights from gene expression data. We developed Transcriptional Regulator Identification using Prize-collecting Steiner trees (TRIPS), a workflow for identifying candidate transcriptional regulators from case-control expression data. In the first step, TRIPS combines the results of differential expression analysis with a disease module identification step to retrieve perturbed subnetworks comprising an expanded gene list. TRIPS then solves a prize-collecting Steiner tree problem on a gene regulatory network, thereby identifying candidate transcriptional modules and transcription factors. We compare TRIPS to relevant methods using publicly available disease datasets and show that the proposed workflow can recover known disease-associated transcription factors with high precision. Network perturbation analyses demonstrate the reliability of TRIPS results. We further evaluate TRIPS on Alzheimer’s disease, diabetic kidney disease, and prostate cancer single-cell omics datasets. Overall, TRIPS is a useful approach for prioritizing transcriptional mechanisms for further downstream analyses.

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Section: Application To Alzheimer's Diseasementioning

confidence: 99%

Identification of transcriptional regulators using a combined disease module identification and prize-collecting Steiner tree approach

Galindez,

Lopez,

Blumenthal

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…AD-induced phagocytic microglia express a specific profile of miRNAs. For AD mice (5xFAD), Aβ-laden microglia were isolated from the brains for RNA sequencing to analyze the transcriptional changes in phagocytic microglia; the specific miRNA profile included the downregulation of miR-7a-5p, miR-29a-3p, and miR-146a-5p, and the upregulation of miR-155-5p and miR-211-5p [ 60 ]. In APP/PS1 mice, miR-146a overexpression switched the microglial phenotype, reduced the number of pro-inflammatory cytokines, enhanced the phagocytic function, and reduced the Aβ levels, leading to a reduction in animal cognitive deficits [ 61 ], despite conflicting evidence from different models [ 62 ].…”

Section: Mirna Regulation In Microglia and Macrophages In Gbm And Admentioning

confidence: 99%

Comparative Insight into Microglia/Macrophages-Associated Pathways in Glioblastoma and Alzheimer’s Disease

Shi,

Huang

2023

IJMS

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Microglia and macrophages are pivotal to the brain’s innate immune response and have garnered considerable attention in the context of glioblastoma (GBM) and Alzheimer’s disease (AD) research. This review delineates the complex roles of these cells within the neuropathological landscape, focusing on a range of signaling pathways—namely, NF-κB, microRNAs (miRNAs), and TREM2—that regulate the behavior of tumor-associated macrophages (TAMs) in GBM and disease-associated microglia (DAMs) in AD. These pathways are critical to the processes of neuroinflammation, angiogenesis, and apoptosis, which are hallmarks of GBM and AD. We concentrate on the multifaceted regulation of TAMs by NF-κB signaling in GBM, the influence of TREM2 on DAMs’ responses to amyloid-beta deposition, and the modulation of both TAMs and DAMs by GBM- and AD-related miRNAs. Incorporating recent advancements in molecular biology, immunology, and AI techniques, through a detailed exploration of these molecular mechanisms, we aim to shed light on their distinct and overlapping regulatory functions in GBM and AD. The review culminates with a discussion on how insights into NF-κB, miRNAs, and TREM2 signaling may inform novel therapeutic approaches targeting microglia and macrophages in these neurodegenerative and neoplastic conditions. This comparative analysis underscores the potential for new, targeted treatments, offering a roadmap for future research aimed at mitigating the progression of these complex diseases.

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Simple gangliosides co-localize with amyloid plaques and increase with age in a transgenic mouse model of Alzheimer’s disease

Wang,

Myers,

Ollen-Bittle

et al. 2024

Preprint

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease accounting for two-thirds of all dementia cases, and age is the strongest risk factor. Beyond the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a class of membrane lipids of the glycosphingolipid family and are enriched in the central nervous system (CNS). Ganglioside dysregulation has been implicated in various neurodegenerative diseases, including AD, but the spatial distribution with respect to amyloid-beta (Aβ) deposition is not well understood. To address this gap, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was employed to investigate the age-dependent expression profile of A-series ganglioside species GD1a, GM1, GM2, and GM3 in the APP/PS1 transgenic mouse model of AD that develops age-dependent amyloid-beta (Aβ) plaques. This study utilized a dual resolution approach combining whole brain imaging for comprehensive detection of ganglioside expression across neuroanatomical regions with high-resolution imaging of the cerebral cortex and hippocampus to interrogate plaque-associated ganglioside alterations. Results showed age-dependent changes in the complex gangliosides GM1 and GD1a across white and grey matter regions in both wildtype and APP/PS1 mice. Significantly higher levels of simple gangliosides GM2 and GM3 were observed in transgenic mice at 12 and 18 months compared to age-matched controls in the cortex and dentate gyrus of the hippocampus. Accumulation of GM3 co-localized with Aβ plaques in the aged APP/PS1 mice, and correlated with Hexa gene expression supporting ganglioside degradation as a mechanism for the accumulation of GM3 This work is the first to demonstrate that age-related ganglioside dysregulation is spatiotemporally associated with Aβ plaques using sophisticated MSI and reveals novel mechanistic insights underlying lipid regulation in AD.

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Alzheimer's disease‐induced phagocytic microglia express a specific profile of coding and non‐coding RNAs

Cited by 3 publications

References 72 publications

Identification of transcriptional regulators using a combined disease module identification and prize-collecting Steiner tree approach

Identification of transcriptional regulators using a combined disease module identification and prize-collecting Steiner tree approach

Comparative Insight into Microglia/Macrophages-Associated Pathways in Glioblastoma and Alzheimer’s Disease

Simple gangliosides co-localize with amyloid plaques and increase with age in a transgenic mouse model of Alzheimer’s disease

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