RT Journal Article
SR Electronic
T1 Neurons burdened by DNA double strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.23.474002
DO 10.1101/2021.12.23.474002
A1 Gwyneth Welch
A1 Carles Boix
A1 Eloi Schmauch
A1 Jose Davila-Velderrain
A1 Matheus B. Victor
A1 Vishnu Dileep
A1 Lorenzo Bozzelli
A1 Qiao Su
A1 Jemmie Cheng
A1 Audrey Lee
A1 Noelle Leary
A1 Andreas Pfenning
A1 Manolis Kellis
A1 Li-Huei Tsai
YR 2021
UL http://biorxiv.org/content/early/2021/12/23/2021.12.23.474002.abstract
AB DNA double strand breaks (DSBs) are linked to aging, neurodegeneration, and senescence1,2. However, the role played by neurons burdened with DSBs in disease-associated neuroinflammation is not well understood. Here, we isolate neurons harboring DSBs from the CK-p25 mouse model of neurodegeneration through fluorescence-activated nuclei sorting (FANS), and characterize their transcriptomes using single-nucleus, bulk, and spatial sequencing techniques. We find that neurons harboring DSBs enter a late-stage DNA damage response marked by the activation of senescent and antiviral-like immune pathways. We identify the NFkB transcription factor as a master regulator of immune gene expression in DSB-bearing neurons, and find that the expression of cytokines like Cxcl10 and Ccl2 develop in DSB-bearing neurons before glial cell types. Alzheimer’s Disease pathology is significantly associated with immune activation in excitatory neurons, and direct purification of DSB-bearing neurons from Alzheimer’s Disease brain tissue further validates immune gene upregulation. Spatial transcriptomics reveal that regions of brain tissue dense with DSB-bearing neurons also harbor signatures of inflammatory microglia, which is ameliorated by NFkB knock down in neurons. Inhibition of NFkB or depletion of Ccl2 and Cxcl10 in DSB-bearing neurons also reduces microglial activation in organotypic brain slice culture. In conclusion, we find that in the context of age-associated neurodegenerative disease, DSBs activate immune pathways in neurons, which in turn adopt a senescence associated secretory phenotype to elicit microglia activation. These findings highlight a novel role for neurons in the mechanism of age-associated neuroinflammation.Summary It is unclear how age-associated DNA double strand break (DSB) accumulation in neurons influences the progression of cellular senescence and neurodegenerative disease. Here, we leverage mouse models of neurodegeneration, single-nucleus, bulk, and spatial transcriptomics from Alzheimer’s disease patients, mouse models, and primary neuron cultures to dissect the immune signaling pathways initiated by DSB-bearing neurons that trigger neuroinflammation.Competing Interest StatementThe authors have declared no competing interest.