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.