Senescent astrocytes identified as key drivers of Alzheimer's progression

Researchers from the NeuroAD group (Neuropathology of Alzheimer's Disease) within the Department of Cell Biology, Genetics and Physiology at the University of Málaga, also affiliated with IBIMA-BIONAND Platform and CIBERNED, have made a pioneering breakthrough in the fight against this disease by identifying astrocytes as a promising cellular target for the development of future therapies.

The study demonstrates, for the first time, the presence of senescent astrocytes - cells that remain alive but have lost their functional capacity - in the brains of Alzheimer's patients, positioning this cellular aging process as a key mechanism in neurodegeneration.

The research, published in the prestigious journal Journal of Neuroinflammation, was led by Dr. Antonia Gutiérrez, Professor of Cell Biology and Principal Investigator of the NeuroAD group, together with Dr. Juan Antonio García León, Associate Professor of Cell Biology. Other contributors to the study include Laura Cáceres, Laura Trujillo, Elba López, Elisabeth Sánchez, and Inés Moreno.

Astrocytes are the most abundant glial cells in the brain and play an essential role in maintaining and protecting neurons, ensuring their survival and proper functioning. However, the research reveals that in patients carrying the highest genetic risk genotype for Alzheimer's disease (APOE4), these cells undergo premature pathological 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.

Cutting-edge technology: From skin to brain

To reach these conclusions, the team employed advanced technology based on induced pluripotent stem cells (iPSCs). From small skin samples obtained from patients, researchers successfully reprogrammed these cells in the laboratory into functional human astrocytes.

This strategy enabled the direct study of disease mechanisms in human cells, overcoming the limitations of animal models, which do not always faithfully reproduce the complexity of the human brain.

The in vitro findings were subsequently validated through the analysis of postmortem brain tissue from Alzheimer's patients. This study confirmed that nearly 80% of the cells displaying signs of premature aging in the cerebral cortex corresponded to astrocytes - a significantly higher proportion than that observed in healthy individuals of the same age.

These results strongly reinforce the hypothesis that astrocyte senescence is not a secondary phenomenon, but rather a central element in disease progression.

Toward new therapies

This discovery is particularly significant in a context where no effective treatment currently exists to cure or halt the progression of Alzheimer's disease, a condition affecting more than 1.2 million people in Spain alone.

The study's findings open a promising new avenue based on the development of innovative therapeutic strategies - such as senolytic drugs - aimed at eliminating or "reprogramming" these aged astrocytes in order to protect neurons and slow cognitive decline.

The research forms part of the doctoral thesis of Laura Cáceres Palomo, first author of the study, and involved collaboration with researchers from internationally renowned institutions such as the University of California, Irvine (UCI) and the University of California, San Francisco (UCSF), as well as the University of Seville (US), the Institute of Biomedicine of Seville (IBIS), and CIBERNED, highlighting the multidisciplinary and global nature of the investigation.