Nature Genetics · 1 new citation this week and rising on Discover.

Polzer and colleagues show that neuronal miR-124 delivery remodels the dentate gyrus in an Alzheimer's disease model. Early-stage treatment reduced mature granule-cell excitability, altered dendrites, downregulated synaptic gene target networks, and increased immature neurons and microglia; later-stage treatment reduced Aβ40/Aβ42, plaques, and plaque-associated microglial responses, supporting a multifaceted miR-124-mediated neuroprotection.

Scientists have engineered an MG1 peptide-targeted liposome that delivers aspirin-triggered resolvin D1 to spinal microglia, reprogramming them via a newly discovered ANGPTL4-SUCLG1-propionate axis to

Read the full paper: Microglia-mediated extracellular matrix disruption drives neuronal dysfunction, motor impairments, and sedation following alcohol abuse

Microglia rely on lysosomes to clear phagocytosed material and orchestrate immune responses, but the mechanisms governing glial lysosome diversity and function remain largely undefined. Using high-res...

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Alcohol’s brain effects are attributed to neurons, leaving microglial functional involvement untested. Paouri, Stanko, et al. show that microglia drive alcohol-induced sedation, motor impairment, and ...

Read the full paper: Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi–Goutières syndrome neuropathology

<div xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="section"><a class="named-anchor" id="d13131116e129"><!-- named anchor --></a><h5 class="section-title" id="d13131116e130">Background:</h5><p dir="auto" id="d13131116e132">In multiple sclerosis (MS), chronic “smoldering” lesions are driven by microglial activation, which promotes demyelination and disease progression. However, microglia exhibit a functional dichotomy by performing both neurotoxic and reparative roles. Precisely modulating these functions remains a major therapeutic challenge, because non-specific approaches can inadvertently impair beneficial microglial functions. Delineating microglial subtypes in chronic MS is therefore essential for targeted therapy.</p></div><div xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="section"><a class="named-anchor" id="d13131116e134"><!-- named anchor --></a><h5 class="section-title" id="d13131116e135">Methods:</h5><p dir="auto" id="d13131116e137">Single-cell RNA sequencing, spatial transcriptomics, deconvolution, and pseudotime trajectory mapping were used to characterize cell subtypes. Subsequent investigations encompassed functional annotation, differential gene expression profiling, cell-cell communication pathways, and transcription factor network analysis.</p></div><div xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="section"><a class="named-anchor" id="d13131116e139"><!-- named anchor --></a><h5 class="section-title" id="d13131116e140">Results:</h5><p dir="auto" id="d13131116e142">We identified six distinct microglial subtypes with varied functions and focused on the highly disease-relevant C2 microglial subtype. This subtype simultaneously exhibited enhanced phagocytic and pro-inflammatory functions potentially associated with the fatty acid metabolic pathway. Pseudotime trajectory analysis suggested that this subtype is likely to represent a late disease stage. Cell-cell communication analysis revealed interactions between this subtype and both oligodendrocytes and T cells, as further supported by spatial transcriptomics demonstrating co-localization of the C2 microglial subtype with T cells. Finally, transcriptional regulatory network analysis identified an association between the FOSL2 regulon and both the C2 microglial subtype and chronic MS.</p></div><div xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="section"><a class="named-anchor" id="d13131116e144"><!-- named anchor --></a><h5 class="section-title" id="d13131116e145">Conclusion:</h5><p dir="auto" id="d13131116e147">Through integrated single-cell sequencing approaches, we identified a C2 microglial subtype in chronic MS that might contribute to disease progression via pro-inflammatory functions. We propose the transcription factor FOSL2 as a promising hypothesis-generating candidate for future studies aimed at modulating microglial differentiation toward a less harmful state. Our findings provide mechanistic insights into the pathology of white matter lesions in chronic MS and suggest novel subtype-specific directions for the development of next-generation disease-modifying therapies.</p></div>

Read the full paper: CAR-engineered microglia harness phagocytosis to target brain tumor in organoid models

Microglia clear intraneuronal α-synuclein aggregates.

Cowley et al. show that CNS-penetrant, selective P2X7 receptor antagonists reduce the release of pro-inflammatory cytokines from human microglia and brain