Neuroinflammation in Alzheimer disease

Nature reviews. Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

Language: Английский

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Traffic-related diesel pollution particles impair the lysosomal functions of human iPSC-derived microglia

Environment International, Journal Year: 2025, Volume and Issue: 199, P. 109467 - 109467

Published: May 1, 2025

Language: Английский

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CRISPRi-based screen of autism spectrum disorder risk genes in microglia uncovers roles of ADNP in microglia endocytosis and synaptic pruning

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: April 6, 2025

Abstract Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with complex biology. The identification ASD risk genes from exome-wide association studies and de novo variation analyses has enabled mechanistic investigations into how ASD-risk alter development. Most functional genomics have focused on the role these in neurons neural progenitor cells. However, roles for other cell types largely uncharacterized. There is evidence postmortem tissue that microglia, resident immune cells brain, appear activated ASD. Here, we used CRISPRi-based to systematically assess impact gene knockdown microglia activation phagocytosis. We developed an iPSC-derived microglia-neuron coculture system high-throughput flow cytometry readout synaptic pruning enable parallel screening phagocytosis beads, synaptosomes, pruning. Our screen identified ADNP , high-confidence genes, as modifier microglial found loss altered endocytic trafficking, remodeled proteomes, increased motility coculture.

Language: Английский

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The proteomic landscape of microglia in health and disease

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: March 15, 2024

Microglia are the resident immune cells of central nervous system (CNS) and as such play crucial roles in regulating brain homeostasis. Their presence neurodegenerative diseases is known, with neurodegeneration-associated risk genes heavily expressed microglia, highlighting their importance contributing to disease pathogenesis. Transcriptomics studies have uncovered heterogeneous landscape microglia health disease, identifying important disease-associated signatures DAM, insight into both regional temporal diversity phenotypes. Quantitative mass spectrometry methods ever increasing field neurodegeneration, utilised ways identify biomarkers gain deeper understanding pathology. Proteins main mechanistic indicators cellular function, yet discordance between transcript proteomic findings has highlighted need for in-depth phenotypic functional analysis fully understand kinetics at molecular level. This review details current progress using proteomics define biology, relationship gene protein expression future emerging aiming resolve cell landscapes.

Language: Английский

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Age-Related Neurodegenerative Diseases: A Stem Cell’s Perspective

Cells, Journal Year: 2025, Volume and Issue: 14(5), P. 347 - 347

Published: Feb. 27, 2025

Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and concomitant decline in neurological function. Examples this type clinical condition are Alzheimer's Disease, Parkinson's Huntington's Disease Amyotrophic Lateral Sclerosis. Age has been identified as major risk the etiology these which explains their increased incidence developed countries. Unfortunately, despite continued intensive efforts, no cure yet found for any diseases; reliable markers that allow an early diagnosis disease identification key molecular events leading to onset progression lacking. Altered adult neurogenesis appears precede appearance severe symptoms. Given scarcity human samples considerable differences with model species, increasingly complex stem-cell-based models being developed. These shedding light on alterations contribute development, facilitating new targets providing screening platform testing candidate drugs. Moreover, secretome other promising features cell types explored, use them replacement cells high plasticity or co-adjuvant therapy combinatorial treatments.

Language: Английский

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The Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins Protects Against Microglia-Mediated Neuronal Loss In Vitro

Biomolecules, Journal Year: 2025, Volume and Issue: 15(4), P. 528 - 528

Published: April 4, 2025

Neuroinflammation is a key feature of all neurodegenerative disorders, including Alzheimer's disease, and tightly regulated by epigenetic mechanisms. Among them, bromodomain extraterminal domain (BET) proteins play crucial role recognizing acetylated histones acting as transcriptional co-regulators to modulate gene expression. This study investigates the potential inhibiting BET in preventing microglia-mediated neuronal damage vitro. Murine BV2 microglial cells were exposed lipopolysaccharide (LPS) or amyloid-β (Aβ) induce an inflammatory response, subsequent effects on murine HT22 examined. tested, only Brd4 was significantly upregulated upon pro-inflammatory stimulation. JQ1, potent pan-inhibitor proteins, suppressed LPS-induced upregulation cytokine mRNA levels, Il1b, Il6, Tnf, microglia. Pre-treatment with JQ1 attenuated cytotoxicity LPS-activated toward neurons. Additionally, conditioned media from Aβ fibril-stimulated induced cell death, which partially prevented pre-treatment JQ1. Co-culture assays further demonstrated beneficial effect inhibition. Our findings suggest that targeting may offer neuroprotective strategy modulating activation, potentially providing therapeutic benefits diseases.

Language: Английский

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A proteogenomic tool uncovers protein markers for human microglial states

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: May 2, 2025

Human microglial heterogeneity has been largely described using transcriptomic data. Here, we introduce a proteomic data resource and Cellular Indexing of Transcriptomes Epitopes by Sequencing panel enhanced with antibodies targeting 17 cell surface proteins (mCITE-Seq). We evaluated mCITE-Seq on HMC3 microglia-like cells, induced-pluripotent stem cell-derived microglia (iMG), freshly isolated primary human microglia. identified novel protein markers such as CD51 relate expression 101 to transcriptional programs. This results in the identification validation three marker combinations which purify enriched each 23 programs; for example, CD49D, HLA-DR CD32 enrich GPNMB^high (“disease associated”) Further, identify validate - SIRPA, PDPN CD162 – that differentiate from infiltrating macrophages. The enables transition RNA-based classification facilitates functional characterization harmonization model systems.

Language: Английский

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Microglia transcriptional states and their functional significance: Context drives diversity

Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

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CRISPRi-based screen of Autism Spectrum Disorder risk genes in microglia uncovers roles ofADNPin microglia endocytosis and uptake of synaptic material

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with complex biology. The identification ASD risk genes from exome-wide association studies and de novo variation analyses has enabled mechanistic investigations into how ASD-risk alter development. Most functional genomics have focused on the role these in neurons neural progenitor cells. However, roles for other cell types largely uncharacterized. There is evidence postmortem tissue that microglia, resident immune cells brain, appear activated ASD. Here, we used CRISPRi-based to systematically assess impact gene knockdown microglia activation phagocytosis. We developed an iPSC-derived microglia-neuron coculture system high-throughput flow cytometry readout synaptic pruning enable parallel screening phagocytosis beads, synaptosomes, pruning. Our screen identified

Language: Английский

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Deep Proteome Coverage of Microglia Using a Streamlined Data-Independent Acquisition-Based Proteomic Workflow: Method Consideration for a Phenotypically Diverse Cell Type

Proteomes, Journal Year: 2024, Volume and Issue: 12(4), P. 35 - 35

Published: Nov. 27, 2024

As the primary innate immune cells of brain, microglia play a key role in various homeostatic and disease-related processes. To carry out their numerous functions, adopt wide range phenotypic states. The proteomic landscape represents more accurate molecular representation these phenotypes; however, present unique challenges for analysis. This study implemented streamlined liquid- gas-phase fractionation method with data-dependent acquisition (DDA) parallel accumulation–serial fragmentation (PASEF) analysis on TIMS-TOF instrument to compile comprehensive protein library obtained from adult-derived, immortalized mouse low starting material (10 µg). empirical consisted 9140 microglial proteins was utilized identify an average 7264 proteins/run single-shot, data-independent (DIA)-based cell lysate digest (200 ng). Additionally, predicted facilitated identification 7519 same DIA data, revealing complementary coverage compared collectively increasing approximately 8000 proteins. Importantly, several microglia-relevant pathways were uniquely identified approach. Overall, we report simplified, reproducible approach address proteome complexity using sample input show importance optimization this phenotypically diverse type.

Language: Английский

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