DNA double strand breaks (DSBs), neuroinflammation, and vascular alterations in the brain are all associated with neurodegenerative disorders. However, it remains unclear how these neuropathological changes relate to each other and act synergistically to promote neurodegeneration. Here we reveal cerebrovascular defects caused by abrogating the BRCA1-assocaited protein Brap in cerebral cortical neurons in mice. Brap loss of function results in persistent DSBs and a senescence state in cortical neurons. In this state, upregulation of genes involving in cell secretion as well as encoding inflammatory and vasoactive factors leads to both ischemic and hemorrhagic damages to cerebral blood vessels. The vascular lesions intertwine with neuroinflammation and neuronal DSBs. They impair glycolytic metabolism, increase oxidative stress, and exacerbate neuronal DSBs, resulting in downregulation of genes essential for neuronal function. By demonstrating the non-cell-autonomous cerebrovascular impact of damaged neurons, our data suggest that DSBs can initiate brain-wide neurodegeneration through senescence-mediated secretion.
SummaryNeurons in the neocortex are generated during embryonic development. While the adult ventricular-subventricular zone (V-SVZ) contains cells with neural stem/progenitors’ characteristics, it remains unclear whether it has the capacity of producing neocortical neurons. Here we show that the generation of neurons exhibiting transcriptomic resemblance to neurons of the upper cortical layers continues in the V-SVZ of mouse models of a human condition known as periventricular heterotopia by abrogating filamin. We found such surplus neurogenesis was associated with V-SVZ’s transcriptional upregulation of oxidative phosphorylation, mitochondrial biogenesis, and increased vascularization. Our spatial transcriptomics analysis also showed that the neurogenic activation of V-SVZ was coupled with enriched expression of genes in diverse pathways for energetics, signaling, neuronal activities, and metabolic turnovers of nucleic acids and proteins in upper cortical layers. These findings support the potential of generating neocortical neurons in adulthood through enhancing brain-wide vascular circulation, aerobic ATP synthesis, and neuronal vitality.
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