Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer's disease.
Cell Stem Cell
; 29(12): 1637-1652.e6, 2022 12 01.
Article
en En
| MEDLINE
| ID: mdl-36459967
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Enfermedad de Alzheimer
Límite:
Aged
/
Humans
Idioma:
En
Revista:
Cell Stem Cell
Año:
2022
Tipo del documento:
Article