Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease

• Published in: Cell stem cell 2022-12, Vol.29 (12), p.1637-1652.e6
• Main Authors: Herdy, Joseph R., Traxler, Larissa, Agarwal, Ravi K., Karbacher, Lukas, Schlachetzki, Johannes C.M., Boehnke, Lena, Zangwill, Dina, Galasko, Doug, Glass, Christopher K., Mertens, Jerome, Gage, Fred H.
• Format: Article
• Language: English
• Subjects: Aged; aging; Alzheimer Disease; Alzheimer’s disease; Astrocytes; Brain; Humans; induced neurons (iNs); inflammation; Neurons; Oncogenes; SASP; senescence; senolytics
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2022.11.010

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. [Display omitted] •Aged, induced neurons (iNs) endogenously present features of cellular senescence•Alzheimer’s neurons senesce more frequently than healthy controls•Senescent neurons gain an inflammatory senescence-associated secretory phenotype•Senescent neurons can be eliminated with senotherapeutics Herdy et al. identify an enriched population of senescent neurons in the Alzheimer’s brain, which can be modeled in vitro using induced neurons (iNs) and eliminated with senotherapeutics. Alzheimer’s iNs present molecular and genetic markers of senescence and an inflammatory secretome that can trigger reactive astrogliosis.