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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

UK Pilot Study Suggests Digital Pathway May Expand BRCA Testing in Breast Cancer

A randomized pilot study in the Journal of Medical Genetics points to similar outcomes for breast cancer patients receiving germline BRCA testing through fully digital or partially digital testing pathways.

Survey Sees Genetic Literacy on the Rise, Though Further Education Needed

Survey participants appear to have higher genetic familiarity, knowledge, and skills compared to 2013, though 'room for improvement' remains, an AJHG paper finds.

Study Reveals Molecular, Clinical Features in Colorectal Cancer Cases Involving Multiple Primary Tumors

Researchers compare mismatch repair, microsatellite instability, and tumor mutation burden patterns in synchronous multiple- or single primary colorectal cancers.

FarGen Phase One Sequences Exomes of Nearly 500 From Faroe Islands

The analysis in the European Journal of Human Genetics finds few rare variants and limited geographic structure among Faroese individuals.