NeuralCipher Research overview
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Abstract Aging has a critical role in the development of neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. In the current study, we investigated the impact of aging on the brain through telomere shortening, a physiological change correlated with aging. Animals with shortened telomeres exhibit cognitive decline and exacerbated lipofuscinosis in the brain. Our single-nuclei transcriptome analysis revealed that telomere shortening led to the emergence of a senescent microglia population reminiscent of a senescence-associated secretory phenotype signature, and oligodendrocyte lineage cells with disrupted maturation and differentiation profiles. Using iPSC-derived microglia with shortened telomeres, we identified DLK1 as a novel senescence-associated ligand secreted by senescent microglia. Depletion of microglia abolished the DLK1 elevation in the cerebral spinal fluid of telomere-shortened mice. Elevation of soluble DLK1 induced demyelination and disruption of neuronal calcium signaling. Our findings highlighted the induction of microglia senescence by telomere shortening and identified DLK1 as a new senescence-associated ligand by which senescent microglia disrupts normal myelination and neuronal calcium activity.
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