Alzheimer’s disease (AD) is a progressive brain disorder marked by the buildup of a protein called Aβ, along with inflammation and damage to nerve cells. In the early stages of AD, before noticeable nerve damage occurs, reactive astrocytes—star-shaped cells in the brain—become active in response to toxic protein clumps.
However, how reactive astrocytes contribute to brain damage through non-cell autonomous mechanisms isn’t fully understood.
A research team led by Dr. Hoon Ryu from the Korea Institute of Science and Technology (KIST, President Sang-Rok Oh) Brain Disease Research Group, in collaboration with Director Justin C. Lee of the Institute for Basic Science (IBS, President Do-Young Noh) and Professor Junghee Lee from Boston University Chobanian & Avedisian School of Medicine, has uncovered a new mechanism involving astrocytes for treating Alzheimer’s disease (AD) and proposed a novel therapeutic target.
In this study, researchers found that the autophagy pathway in astrocytes (the brain’s non-neuronal cells) helps clear away amyloid-beta (Aβ) oligomers, the toxic proteins linked to Alzheimer’s disease. This process improves memory and cognitive functions.
Autophagy is a process in which cells break down and recycle their parts to maintain balance. In this study, researchers examined how autophagy works in astrocytes. They found that when toxic proteins build up, or inflammation occurs in the brains of Alzheimer’s patients, astrocytes activate genes that control autophagy. By introducing these autophagy-related genes specifically into astrocytes in mouse models of Alzheimer’s, the team observed recovery in damaged neurons.
The study showed that astrocytic autophagy helps reduce amyloid-beta (Aβ) aggregates (protein clumps) and improves memory and cognitive functions. When these autophagy-related genes were expressed in astrocytes in the hippocampus—a brain area crucial for memory—the symptoms of brain damage decreased.
Most importantly, this research highlighted that the ability of astrocytes to adapt their autophagy processes plays a crucial role in removing Aβ oligomers, a significant contributor to Alzheimer’s disease. This suggests a promising new approach for treating the condition.
This research is significant because it moves away from the usual focus on neurons in Alzheimer’s drug development, highlighting astrocytes (non-neuronal cells) as a new target for therapy. The research team aims to explore drug developments that can boost the autophagic function of astrocytes to help prevent or reduce dementia symptoms. They also plan to conduct preclinical studies shortly.
Dr. Hoon Ryu from the Korea Institute of Science and Technology (KIST, President Sang-Rok Oh) Brain Disease Research Group said, “Our findings show that astrocytic autophagy restores neuronal damage and cognitive functions in the dementia brain. We hope this study will advance our understanding of cellular mechanisms related to autophagy and contribute to future research on waste removal by astrocytes and health maintenance of the brain.”
Journal Reference:
- Kim, S., Chun, H., Kim, Y. et al. Astrocytic autophagy plasticity modulates Aβ clearance and cognitive function in Alzheimer’s disease. Mol Neurodegeneration 19, 55 (2024). DOI: 10.1186/s13024-024-00740-w