Researchers at Washington University School of Medicine in St. Louis have developed a method to study aged neurons in the lab without the need for a brain biopsy, aiming to capture the effects of aging in the development of Alzheimer’s disease. Late-onset Alzheimer’s disease, the most common type of Alzheimer’s, was the focus of the study, with the researchers successfully transforming skin cells from patients with the disease into neurons that accurately reproduced hallmarks of the condition such as amyloid beta buildup, tau protein deposits, and neuronal cell death. This advancement could lead to a better understanding of the disease and new treatment strategies.
The findings of the study, published in the journal Science, highlight the role of retrotransposable elements in the genome of cells in the development of late-onset Alzheimer’s disease. These elements, which change their activity as we age, were identified as potential targets for new treatment strategies to combat the disease. Animal studies of Alzheimer’s disease have traditionally focused on rare genetic mutations causing early-onset Alzheimer’s, making it challenging to study the more common late-onset form. The newly developed method of cellular reprogramming with human skin cells allows for a more accurate representation of the disease to be studied in the lab.
After transforming skin cells into brain cells, the researchers observed that the resulting neurons could grow in a gel layer or self-assemble into clusters mimicking the 3D environment of the brain. Spheroids generated from Alzheimer’s disease patients quickly developed amyloid beta deposits and tau tangles, as well as signs of inflammation and neuronal death, closely mirroring what is seen in brain scans of patients. The study also compared spheroids from healthy individuals of similar ages, finding evidence that the technique captures the effects of aging on cells and suggests a correlation between amyloid beta and tau accumulation with aging.
Treatment of late-onset Alzheimer’s disease spheroids with drugs targeting amyloid beta plaques early in the disease process significantly reduced deposits, emphasizing the importance of early detection and intervention in treating the disease. The study also found that inhibiting retrotransposable elements with a drug called lamivudine had a positive effect on reducing amyloid beta and tau tangles as well as neuronal death in spheroids from late-onset Alzheimer’s patients. This suggests that elements associated with aging play a distinct role in the development of sporadic late-onset Alzheimer’s compared to inherited early-onset Alzheimer’s.
Future studies will focus on expanding the model system to include multiple types of brain cells, such as neurons and glia, to further understand the pathology of late-onset Alzheimer’s disease. The researchers plan to work towards developing personalized therapeutic interventions for the condition based on the insights gained from this study. An application for a U.S. patent related to the work has been filed by Washington University, showcasing the potential for novel approaches to studying and treating Alzheimer’s disease using this innovative method of direct neuronal reprogramming. The study was supported by various organizations and grants, highlighting the importance of collaborative efforts in advancing research on Alzheimer’s disease.