Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease
Cell Stem Cell, 2022
Herdy J., Traxler L., Agarwal R., Karbacher L., Schlachetzki J., Boehnke L., Zangwill D., Galasko D., Glass C., Mertens J., Gage F.
Disease area | Application area | Sample type | Products |
---|---|---|---|
Neurology | Pathophysiology | Cell Culture Supernatant CSF | Olink Target 96 |
Abstract
The concept of senescence as a phenomenon limited to proliferating cells has been challenged by growing evidence of senescence-like features in terminally differentiated cells, including neurons. The persistence of senescent cells late in life is associated with tissue dysfunction and increased risk of age-related disease. We found that Alzheimer’s disease (AD) brains have significantly higher proportions of neurons that express senescence markers, and their distribution indicates bystander effects. AD patient-derived directly induced neurons (iNs) exhibit strong transcriptomic, epigenetic, and molecular biomarker signatures, indicating a specific human neuronal senescence-like state. AD iN single-cell transcriptomics revealed that senescent-like neurons face oncogenic challenges and metabolic dysfunction as well as display a pro-inflammatory signature. Integrative profiling of the inflammatory secretome of AD iNs and patient cerebral spinal fluid revealed a neuronal senescence-associated secretory phenotype that could trigger astrogliosis in human astrocytes. Finally, we show that targeting senescence-like neurons with senotherapeutics could be a strategy for preventing or treating AD.