A new study from researchers highlights an unexpected player in Alzheimer's disease: aging astrocytes.
Senescent astrocytes have been identified as a major contributor to Alzheimer's progression. The cells lose protective functions and fuel inflammation, particularly in APOE4 carriers. The findings highlight senolytic drugs as a potential new therapy.
For the first time, the research team has shown that senescent astrocytes are present in the brains of people with Alzheimer's disease. These cells remain alive but have lost their normal function, and their accumulation suggests that cellular aging plays a direct and significant role in neurodegeneration.
The findings were published in the Journal of Neuroinflammation. The study was led by Dr. Antonia Gutiérrez, Professor of Cell Biology and Principal Investigator of the NeuroAD group, alongside Dr. Juan Antonio García León, Associate Professor of Cell Biology. The research team also included Laura Cáceres, Laura Trujillo, Elba López, Elisabeth Sánchez, and Inés Moreno.
Astrocytes are the most common type of glial cell in the brain. They are essential for maintaining healthy neurons and supporting proper brain function. However, the researchers found that in individuals with the strongest genetic risk factor for Alzheimer's disease (APOE4), astrocytes show signs of abnormal early aging.
APOE4 Genotype Drives Premature Astrocyte Aging
"We have confirmed that these damaged astrocytes not only lose their ability to protect neurons but also adopt a pro-inflammatory profile that severely compromises neuronal survival," the authors explain. Upon entering a state of senescence, the cells accumulate DNA damage, exhibit mitochondrial alterations—the cellular 'powerhouses'—and 'release toxic molecules that amplify inflammation and tissue damage in the brain.
To investigate these processes, the scientists used induced pluripotent stem cells (iPSCs). By taking small skin samples from patients, they were able to reprogram the cells in the laboratory and generate functional human astrocytes for detailed study.
This approach allowed the team to examine disease mechanisms directly in human cells, avoiding some of the limitations of animal models, which do not always capture the full complexity of the human brain.
Human Validation Confirms Central Role in Neurodegeneration
The laboratory findings were reinforced by examining brain tissue obtained after death from individuals with Alzheimer's disease. The analysis strongly suggested that nearly 80 percent of the cells in the cerebral cortex that displayed signs of premature aging were astrocytes. This proportion was much higher than what is seen in healthy people of the same age.
Together, these results support the idea that astrocyte senescence is not simply a byproduct of the disease but a driving force behind its progression.
The discovery is especially important given that there is currently no effective treatment capable of curing Alzheimer's disease or stopping its advance. In Spain alone, more than 1.2 million people are affected.
The findings suggest a new therapeutic direction focused on developing innovative strategies such as senolytic drugs. These treatments would aim to eliminate or "reprogram" aged astrocytes, with the goal of preserving neurons and slowing cognitive decline.
Reference: "Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support" by Laura Caceres-Palomo, Elisabeth Sanchez-Mejias, Laura Trujillo-Estrada, Juan Jose Perez-Moreno, Elba Lopez-Oliva, Tau En Lim, Leah DeFlitch, Serena H. Chang, Lucas Kampman, M. Ryan Corces, Mathew Blurton-Jones, Ines Moreno-Gonzalez, Alberto Pascual, Javier Vitorica, Juan Antonio Garcia-Leon and Antonia Gutierrez, 12 December 2025, Journal of Neuroinflammation.
DOI: 10.1186/s12974-025-03607-z
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