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Genome Damage in Neurons Triggers Alzheimer's-Linked Inflammation

Neurons overburdened with DNA double-strand breaks trigger neuroinflammation via microglia activation, according to a study appearing in this week's Science Advances, revealing a link between key aspects of age-related neurodegeneration. The accumulation of DSBs in neurons is an early feature of Alzheimer's disease (AD), but the downstream biological effect of this genomic damage is unclear. To investigate, a team led by scientists from the Massachusetts Institute of Technology used bulk and single-nucleus RNA sequencing to transcriptionally characterize neurons burdened with DSBs in a mouse model of neurodegeneration, finding that these neurons activated NFκB-regulated immune signaling pathways similar to senescent cells and neurons infected with a virus. Spatial transcriptomics, meanwhile, revealed regions of the model's brain tissue that were dense with DSB-bearing neurons harboring signatures of inflammatory microglia, which could be ameliorated by NFκB knockdown. NFκB inhibition in DSB-bearing neurons also reduced microglia activation in organotypic mouse brain slice culture. The findings, the study's authors write, suggest that neurons play meaningful roles in neuroinflammation, which historically has been thought to be driven largely by glial cells. "Crucially, this axis of neuron-microglia communication is mediated by DNA damage accumulation in neurons, revealing that two hallmarks of AD, genome fragility and neuroinflammation, are mechanistically linked," they conclude.

The Scan

Positive Framing of Genetic Studies Can Spark Mistrust Among Underrepresented Groups

Researchers in Human Genetics and Genomics Advances report that how researchers describe genomic studies may alienate potential participants.

Small Study of Gene Editing to Treat Sickle Cell Disease

In a Novartis-sponsored study in the New England Journal of Medicine, researchers found that a CRISPR-Cas9-based treatment targeting promoters of genes encoding fetal hemoglobin could reduce disease symptoms.

Gut Microbiome Changes Appear in Infants Before They Develop Eczema, Study Finds

Researchers report in mSystems that infants experienced an enrichment in Clostridium sensu stricto 1 and Finegoldia and a depletion of Bacteroides before developing eczema.

Acute Myeloid Leukemia Treatment Specificity Enhanced With Stem Cell Editing

A study in Nature suggests epitope editing in donor stem cells prior to bone marrow transplants can stave off toxicity when targeting acute myeloid leukemia with immunotherapy.